Handout - Antidepressants and Mood Stabilizer

Medscape Reference
(www.medscape.com)
Antidepressants
Overview
Treatment
Medication
Handout: Lecture Prof. Dr. Dr. Mller
Overview
Practice Essentials..3
Background.......4
Pathophysiology...5
Etiology..6
Epidemiology ...8
Prognosis .....9
Treatment
Approach Considerations 11
Pharmacologic Therapy for Depression ....11
Medication
Medication Summary ...14
Antidepressants, SSRIs ..14
Antidepressants, SNRIs ..15
Antidepressants, TCAs ...16
Antidepressants, MAO Inhibitors ...17
Augmenting Agents .....17
Serotonine-Dopamine Activity Modulators ...18
Antidepressants, Other 18
Stimulants ..18
Thyroid Products ...19
Neurology & Psychiatry, Herbals ...19
Depression: Practice Essentials, Background, Pathophysiology
Depression
Author: Jerry L Halverson, MD; Chief Editor: David Bienenfeld, MD more...
Updated: Jan 27, 2016
Practice Essentials
Major depressive disorder has significant potential morbidity and mortality,
contributing to suicide (see the image below), incidence and adverse outcomes of
medical illness, disruption in interpersonal relationships, substance abuse, and lost
work time. With appropriate treatment, 70-80% of individuals with major depressive
disorder can achieve a significant reduction in symptoms.
From 1991-2006, the suicide rate was consistently higher among males. Suicide rates
declined among both sexes from 1991-2000; the rate among males decreased from 24.64 to
20.67 suicides per 100,000 and 5.48 to 4.62 suicides per 100,000 among females. From
2000-2006, however, the suicide rates gradually increased among females. Note: All rates are
age-adjusted to the standard 2000 population. Rates based on less than 20 deaths are
statistically unreliable. Source: Centers for Disease Control and Prevention. National suicide
statistics at a glance: Trends in suicide rates among persons ages 10 years and older, by sex,
United States, 1991-2006. Available at:
http://www.cdc.gov/violenceprevention/suicide/statistics/trends01.html. Accessed: May 5,
2010.
Signs and symptoms

Most patients with major depressive disorder present with a normal appearance. In
patients with more severe symptoms, a decline in grooming and hygiene may be
observed, as well as a change in weight. Patients may also show the following:
Psychomotor retardation
Flattening or loss of reactivity in the patient's affect (ie, emotional expression)
Psychomotor agitation or restlessness
Major depressive disorder
Among the criteria for a major depressive disorder, at least 5 of the following
symptoms have to have been present during the same 2-week period (and at least 1
of the symptoms must be diminished interest/pleasure or depressed mood)[1] :
Depressed mood: For children and adolescents, this can also be an irritable
mood
Diminished interest or loss of pleasure in almost all activities (anhedonia)
Significant weight change or appetite disturbance: For children, this can be
failure to achieve expected weight gain
Sleep disturbance (insomnia or hypersomnia)
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness
Diminished ability to think or concentrate; indecisiveness
Recurrent thoughts of death, recurrent suicidal ideation without a specific
plan, or a suicide attempt or specific plan for committing suicide
See Clinical Presentation for more detail.
Diagnosis
Screening instruments
Self-report screening instruments for depression include the following:
Patient Health Questionnaire-9 (PHQ-9): A 9-item depression scale; each
item is scored from 0-3, providing a 0-27 severity score.
Beck Depression Inventory (BDI) or the Beck Depression Inventory-II (BDI-II):
21-question symptom-rating scales providing a 0-63 severity score.
BDI for primary care: A 7-question scale adapted from the BDI.
Zung Self-Rating Depression Scale: A 20-item survey.
Center for Epidemiologic Studies-Depression Scale (CES-D): A 20-item
instrument that allows patients to evaluate their feelings, behavior, and
outlook from the previous week.
In contrast to the above self-report scales, the Hamilton Depression Rating Scale
(HDRS) is performed by a trained professional, not the patient. The HDRS has 17 or
http://emedicine.medscape.com/article/286759-overview
21 items, scored from 0-2 or 0-4; a total score of 0-7 is considered normal, while
scores of 20 or higher indicate moderately severe depression.
The Geriatric Depression Scale (GDS), although developed for older adults, has also
been validated in younger adults. The GDS contains 30 items; a short-form GDS has
15 items.
Laboratory studies
No diagnostic laboratory tests are available to diagnose major depressive disorder,
but focused laboratory studies may be useful to exclude potential medical illnesses
that may present as major depressive disorder.
See Workup for more detail.
Management
In all patient populations, the combination of medication and psychotherapy
generally provides the quickest and most sustained response.[2, 3]
Pharmacotherapy
Drugs used for treatment of depression include the following:
Selective serotonin reuptake inhibitors (SSRIs)

Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Atypical antidepressants
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
St. John's wort ( Hypericum perforatum)
Psychotherapy
Evidence-based psychotherapeutic treatments for adults with major depressive
disorder include the following:[4]
Interpersonal psychotherapy (IPT)

Cognitive-behavioral therapy (CBT)
Problem-solving therapy (PST)
Behavioral activation (BA)/contingency management
Evidence-based psychotherapeutic treatments for children and adolescents with

major depressive disorder include the following:[5]
Interpersonal psychotherapy (IPT)
Cognitive-behavioral therapy (CBT)
Behavior therapy (BT)
Many of these treatments incorporate a parent/family component when working with
children or adolescents.
In mild cases, psychosocial interventions are often recommended as first-line
treatments. The American Psychiatric Association (APA) guideline supports this
approach but notes that combining psychotherapy with antidepressant medication
may be more appropriate for patients with moderate to severe major depressive
disorder.[6]
Electroconvulsive therapy
Electroconvulsive therapy (ECT) is a highly effective treatment for depression. The
indications for ECT include the following:
Need for a rapid antidepressant response

Failure of drug therapies
History of good response to ECT
Patient preference
High risk of suicide
High risk of medical morbidity and mortality
Stimulation techniques
Transcranial magnetic stimulation (TMS) is approved by the FDA for treatmentresistant major depression.
Vagus nerve stimulation (VNS) has been approved by the FDA for use in adult
patients who have failed to respond to at least 4 adequate medication and/or ECT
treatment regimens. The stimulation device requires surgical implantation.
See Treatment and Medication for more detail.
Background
As many as two thirds of people with depression do not realize that they have a
treatable illness and therefore do not seek professional help. In addition, persistent
ignorance and misperceptions of the disease by the public, including many health
providers, as a personal weakness or failing that can be willed or wished away leads
to painful stigmatization and avoidance of the diagnosis by many of those affected.
In the primary care setting, where many of these patients first seek treatment, the
presenting complaints often can be somatic, such as fatigue, headache, abdominal
distress, or sleep problems. (See Presentation.)
The American Psychiatric Associations Diagnostic Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5)[1] classifies the depressive disorders as disruptive
mood dysregulation disorder, major depressive disorder (including major depressive
episode), persistent depressive disorder (dysthymia), premenstrual dysphoric
disorder, and depressive disorder due to another medical condition. In addition,
depressive disorders may be further categorized by specifiers that include
peripartum onset, seasonal pattern, melancholic features, mood-congruent or moodincongruent psychotic features, anxious distress, and catatonia. The common
feature of the depressive disorders is the presence of sad, empty, or irritable mood,
accompanied by somatic and cognitive changes that significantly affect the
individuals capacity to function. What differs among them are issues of duration,
timing, or presumed etiology.[1]
The differential diagnosis for depression includes other psychiatric disorders, CNS
diseases, endocrine disorders, drug-related conditions, infectious and inflammatory
diseases, and sleep-related disorders. (See DDx.)
Depression screening tests can be used to screen for depression and bipolar
disorder. The most widely used is the Patient Health Questionnaire-9 (PHQ-9). It is
important to understand that the results obtained from the use of any depression
rating scales are imperfect in any population, especially the geriatric population.
(See Workup.)
Many effective treatments are available for major depressive disorder, including
psychotherapy (eg, cognitive-behavioral therapy, interpersonal psychotherapy,
behavior therapy), used either alone or in combination with medication. However, the
combined approach provides some patients with the quickest and most sustained
response. Uncomplicated depression that is not severe typically responds equally
well to psychotherapy or an antidepressant. (See Treatment.)
There is evidence to support the use of all antidepressants approved by the FDA for
use in major depression, although predicting what an individual patients response to
a particular agent will be is difficult. Assuming adherence to the treatment regimen
and lack of drug or disease-state interactions, treatment for 2-12 weeks at a
therapeutic-dose level is usually needed to achieve a clinical response. The choice
of medication should be guided by anticipated safety and tolerability, physician
familiarity, and personal and family history of previous treatments. (See
Medications.)
This article focuses on major depressive disorder in adults. For information on
depression in children and adolescents, see the Medscape Reference article
Pediatric Depression. For information on depression in bipolar disorder, see Bipolar
Affective Disorder.
Pathophysiology
The underlying pathophysiology of major depressive disorder has not been clearly
defined. Current evidence points to a complex interaction between neurotransmitter
availability and receptor regulation and sensitivity underlying the affective symptoms.
Clinical and preclinical trials suggest a disturbance in central nervous system
serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated
include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived
neurotrophic factor (BDNF).[7] However, drugs that produce only an acute rise in
neurotransmitter availability, such as cocaine or amphetamines, do not have the
efficacy over time that antidepressants do.
The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is
suggested by the therapeutic efficacy of selective serotonin reuptake inhibitors
(SSRIs). In addition, studies have shown that an acute, transient relapse of
depressive symptoms can be produced in research subjects in remission using
tryptophan depletion, which causes a temporary reduction in CNS 5-HT levels.
However, the effect of SSRIs on 5HT reuptake is immediate, but the antidepressant
effect requires exposure of several weeks' duration. Also, some antidepressants
have no effect on 5HT (eg, desipramine), and the antidepressant tianeptine
enhances 5HT uptake. All this, together with preclinical research findings, implies a
role for neuronal receptor regulation, intracellular signaling, and gene expression
over time, in addition to enhanced neurotransmitter availability.
Seasonal affective disorder is a form of major depressive disorder that typically
arises during the fall and winter and resolves during the spring and summer. Studies
suggest that seasonal affective disorder is also mediated by alterations in CNS
levels of 5-HT and appears to be triggered by alterations in circadian rhythm and
sunlight exposure.
Vascular lesions may contribute to depression by disrupting the neural networks
involved in emotion regulationin particular, frontostriatal pathways that link the
dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal
cingulate.[8] Other components of limbic circuitry, in particular the hippocampus and
amygdala, have been implicated in depression.
Brain structures
Functional neuroimaging studies support the hypothesis that the depressed state is
associated with decreased metabolic activity in neocortical structures and increased
metabolic activity in limbic structures.[9] Serotonergic neurons implicated in affective
disorders are found in the dorsal raphe nucleus, the limbic system, and the left
prefrontal cortex.
A meta-analysis comparing brain structures in patients with major depression, in
healthy controls, and in patients with bipolar disorder demonstrated associations
between depression and increased lateral ventricle size, larger cerebrospinal fluid
volume, and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal
lobe, orbitofrontal cortex, and gyrus rectus. Patients experiencing a depressive
episode had smaller hippocampal volume than those in remission.[10]
In one study, positron emission tomographic (PET) images showed abnormally
diminished activity in an area of the prefrontal cortex in patients with unipolar
depression and bipolar depression. This region is related to emotional response and
has widespread connections with other areas of the brain, including the areas that
appear to be responsible for the regulation of DA, noradrenaline (locus ceruleus),
and 5-HT (raphe nuclei).[11]
Both functional and structural abnormalities were found in the same brain region
during a major depressive episode. Sacher et al found increases in glucose
metabolism in the right subgenual and pregenual anterior cingulate cortices and
decreased gray matter volumes in the amygdala, dorsal frontomedian cortex, and
right paracingulate cortex.[11]
Aging
An integrative model of late-onset depression posits that age-related brain changes

and disease-related changes (eg, cerebrovascular disease), coupled with
physiologic vulnerabilities (eg, genetic risk factors, personal history of depression)
and psychosocial adversity, lead to disruptions in the functional circuitry of emotion
regulationnamely, hypometabolism of cortical structures and hypermetabolism of
limbic structures.[8]
Endocrine changes in depression are evident across the life span, but some are
unique to aging. Women with a previous history of depression are at higher risk of
developing depression during menopause, although estrogen replacement does not
relieve depression; low testosterone levels have been associated with depression in
older men.
Etiology
The specific cause of major depressive disorder is not known. As with most
psychiatric disorders, major depressive disorder appears to be a multifactorial and
heterogeneous group of disorders involving both genetic and environmental factors.
Evidence from family and twin studies indicates that with depression that develops in
early childhood, the transmission from parents to children appears to be related
more to psychosocial influences than to genetics.[12] Adolescent-onset and adultonset depression, while more heritable than prepubertal depression, likewise reflect
an interaction between genes and environmental stressors.
Genetics
Genetic factors play an important role in the development of major depression.
Evidence from twin studies suggests that major depression has a concordance of
40-50%. First-degree relatives of depressed individuals are about 3 times as likely to
develop depression as the general population; however, depression can occur in
people without family histories of depression, as well.[13]
Two susceptibility loci have been identified in which no specific gene of interest has
been definitively identified. The MDD1 locus is located at 12q22-q23.2 and is most
strongly linked to major depression in males.[14] The MDD2 locus is located at
15q25.2-q26.2 and has been associated with early onset or recurrent episodes of
depression.[15]
Although multiple genes are likely to influence the susceptibility to depression, those
involved in the serotonin system are a focus of investigation, especially because
many antidepressant medications work by influencing serotonin.[16] The SLC6A4
gene, which is located at 17q11.2, encodes a serotonin transporter (also known as
5-hydroxytryptamine transporter) that is responsible for actively clearing serotonin
from the synaptic space.
A polymorphism in the promoter region of the SLC6A4 gene consists of a 44bp
insertion or deletion involving repeat elements. These polymorphisms are referred to
as either a long allele or a short allele. Caspi et al found that persons who were
homozygous or heterozygous for the short allele had more depressive symptoms
and suicidality in association with stressful life events than those patients who were
homozygous for the long allele.[17]
Other studies also suggest that genes controlling either the production or utilization
of serotonin play an important role in the pathogenesis of depression. The TPH2
gene encodes tryptophan hydroxylase, which is the rate-limiting enzyme in the
synthesis of serotonin. An in vitro study of a TPH2 polymorphism, R441H, found an
approximately 80% loss in serotonin production.
The clinical significance of this polymorphism remains uncertain, however. Zhang et
al found that the allele was more common in a cohort of patients with major
depression than in a control population,[18] but a later study by Garriock et al did not
find any patients with the R441H mutation in a cohort with major depression, a
control group, or a group with bipolar disorder.[19]
The HTR3A and HTR3B regions, which encode serotonin receptors and are located
at chromosome 11q23.2, are also known to be associated with major depression in
both European and Japanese populations. Yamada e al surveyed 29 polymorphisms
located within the HTR3A and HTR3B genes and found a single-nucleotide
polymorphism that was associated with depression in females.[20]
A study of genes in the hypothalamic-pituitary-adrenal axis found that in patients with
major depression, homozygosity for the T allele in the FKBP5 gene was associated
with a quicker response to antidepressants than heterozygosity or homozygosity for
the C allele in that location. However, homozygosity for the T allele was also
associated with an increased recurrence of depressive episodes.[21]
Studies such as those reported by Akiskal and Weller[22] and Weissman et al[23]
suggest a genetic component in the etiology of depressive disorders. Individuals with
a family history of affective disorders, panic disorder, or alcohol dependence carry a
higher risk for major depressive disorder.
Children and adolescents
Nobile et al found that human platelet 5-HT uptake is differentially influenced in
children and adolescents with and without depression by a common genetic variant
of the promoter region of the serotonin transporter gene (5-HTTLPR). Depressed
persons had a lower rate of serotonin uptake and a lower serotonin dissociation
constant[24]
Birmaher et al found that before the onset of affective illness, children who were at
high risk for depression, on the basis of family history, had the same pattern of
neuroendocrine response to infusion of a serotonergic precursor (5-hydroxy-Ltryptophan) challenge as did children with major depression. Compared with low-risk
children, high-risk children and depressed children secreted significantly less cortisol
and, in girls, more prolactin.[25] These findings could constitute the identification of a
trait marker for depression in children.
Late-onset depression
Some evidence suggests that late-onset depression (after age 60 years) is an

etiologically and clinically distinct syndrome[26] and that genetic factors likely play
less of a role in late-onset depression than in early-onset depression. A family
history of depression is less common among patients with late-onset depression
than in younger adults with depression. However, although findings have been
inconsistent, certain genetic markers have been found to be associated with lateonset depression. Such markers include polymorphisms of apolipoprotein E, BDNF,
and 5-HT transporter genes. Interestingly, these markers have also been associated
with cognitive impairment, hippocampal volume, and antidepressant response,
respectively.
Genetic influences on antidepressant drug response
Genetics also play a significant part in the response to pharmacologic treatment of
major depression. A study of the drug transporter gene ABCB1 (which encodes a
transporter glycoprotein and functions as an active efflux pump for a number of
drugs across the blood-brain barrier) found an association between 2 singlenucleotide polymorphisms and achievement of remission with citalopram,
paroxetine, amitriptyline, and venlafaxine. Also, in a mouse model lacking the gene
homologous to the human ABCB1 gene, the mice had significantly higher
concentrations of citalopram, venlafaxine, or desvenlafaxine after 11 days of
subcutaneous administration of the drugs, despite drug plasma concentrations that
were identical to those in mice lacking this mutation.[27]
Approximately 40% of patients who are treated with a selective serotonin reuptake
inhibitor (SSRI) will either discontinue treatment or switch medications because of an
adverse effect of the medication. In one study, an increased risk for sexual
dysfunction from SSRIs was found to be associated with alleles in the 5HT2A and
GHB3 genes.[28]
A study of response to treatment with citalopram identified a significant association
between treatment outcome and a marker in HTR2A, which is located at
chromosome 13q14.2 and encodes the serotonin 2A receptor. The A allele (a singlenucleotide polymorphism in an intron of this gene) reduced the likelihood of
nonresponse to citalopram in whites but not in the African-American population. An
AA genotype resulted in a 16-18% reduction in absolute risk of being a
nonresponder.[29]
Stressors
Although major depressive disorder can arise without any precipitating stressors,
stress and interpersonal losses certainly increase risk. For example, loss of a parent
before the age of 10 years increases the risk of later depression. Cognitivebehavioral models of depression posit that negative cognitions and underlying all-ornothing schemata contribute to and perpetuate depressed mood.[26]
Chronic pain, medical illness, and psychosocial stress can also play a role in major
depressive disorder. Older adults may find medical illness psychologically
distressing, and these illnesses may lead to increased disability, decreased
independence, and disruption of social networks.[30] Chronic aversive symptoms
such as pain associated with chronic medical illness may disrupt sleep and other
biorhythms leading to depression.
Other psychosocial risk factors for depression in late life include the following[31] :
Impaired social supports

Caregiver burden
Loneliness
Bereavement
Negative life events
Cognitive-behavioral models of depression suggest that the presence of negative life

events in addition to ones perception of or reaction to those events may impact the
development and maintenance of depressive symptoms. Cognitive models of
depression posit that negative cognitions and underlying all-or-nothing schemata
contribute to and perpetuate depressed mood.[26] More specifically, cognitive
vulnerability-stress models suggest that, in the face of negative life events,
individuals who have a tendency to make negative attributions about the causes of
those events, about themselves, and about future consequences (in line with the
hopelessness theory of depression) may be more likely to develop depression.[32]
This has been suggested as potentially contributing to gender differences in rates of
depression following puberty (e.g., Hyde, Mezulis, and Abramson[33] ). Behavioral
models suggest that depression may result from deficits in response-contingent
positive reinforcement andinadequate social skills[34] or reliance upon escape and
avoidance behaviors,[35] such that avoidance behaviors in response to negative life
events and corresponding negative emotions may lead to worsened depression.[36]
In addition, neurochemical hypotheses point to the deleterious effects of cortisol and
other stress-related substances on the neuronal substrate of mood in the CNS.
Exposure to certain pharmacologic agents increases the risk of depression, such as
reserpine, beta-blockers, and steroids such as cortisol. Abused substances can also
increase risk of major depressive disorder, such as cocaine, amphetamine,
narcotics, and alcohol. With agents of abuse, however, it is unclear whether
depression is a consequence or facilitator.
Risk-factor interactions
Researchers are currently investigating the relationship between genetic
vulnerability, environmental stressors, and brain structural abnormalities in the
development of depression. In an MRI genetic study, Frodl et al found that patients
with major depression who carried the S allele of 5-HTTLPR and had a history of
childhood emotional neglect had smaller hippocampal volumes than patients who
had only one of those factors. They concluded that structural hippocampal brain
changes resulting from stress may be part of the risk for developing depression and
that these changes are more pronounced in individuals with the S-allele.[37]
Conflicting evidence exists regarding the interaction between the functional serotonin
transporter promoter (5-HTTLPR) and stress in the development of depression. A
2011 meta-analysis suggested that 5-HTTLPR moderates the relationship between
stress and depression.[38] Earlier, smaller meta-analyses had concluded that the
evidence did not support the presence of the interaction.
Neuroendocrine abnormalities and neurodegenerative diseases

Possible abnormalities of the neurotransmitter systems remain under investigation.
Compared with control subjects, depressed prepubertal children had lower cortisol
secretion during the first 4 hours of sleep, according to De Bellis et al. Nocturnal
secretion of adrenocorticotropin, growth hormone, and prolactin did not differ
between the 2 groups.[39]
Potential biological risk factors have been identified for depression in the elderly.
Neurodegenerative diseases (especially Alzheimerdisease and Parkinsondisease),
stroke, multiple sclerosis, seizure disorders, cancer, macular degeneration, and
chronic pain have been associated with higher rates of depression.[40]
Parent-child relations
The parent-child relation model conceptualizes depression as the result of poor
parent-child interaction. Adults with depression report low paternal involvement and
high maternal overprotection during early childhood. Troubled relationships with
parents, siblings, and peers are common in children and adolescents with affective
illness.
Affective illness in a parent may be a factor in child abuse and/or neglect that
promotes affective illness in the child. Childhood abuse and neglect, as well as a
cumulative load of stressors over a lifetime, have been associated with both earlyadult and late-onset depression.
Hammen et al reported a significant temporal association between depression
diagnoses in mother and child.[41] They found that children with substantial stress
exposure who also had symptomatic mothers were significantly more depressed
than children who were exposed to comparable levels of stress only.
Mothers remission from depression, regardless of timing, has a consistently
favorable influence on their children. In the Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) Child study, all children whose mothers experienced
remission from depression showed improvement in mood and behavior in the
following year; children whose mothers recovered from depression within the first 3
months of treatment showed not only improved mood and behavior but significant
improvement in functioning, as well.[42]
Vascular depression
The vascular depression hypothesis posits that cerebrovascular disease may cause
or contribute to late-life depression. Various lines of evidence support this
hypothesis, including the following[43] :
Higher incidence of depression following a left-sided stroke
Higher prevalence of ischemic white-matter changes in older adults with
depression than those without
Bidirectional association between depression and coronary artery disease
and depression and diabetes
Higher rates of depression among patients with vascular dementia than those
with Alzheimer disease
Epidemiology
United States statistics
The lifetime incidence of major depressive disorder in the United States is 20% in
women and 12% in men. The point prevalence is as high as 10% in patients
observed in a medical setting. Klerman[44] and Gershon et al[45] reported a
progressive increase in the incidence of major depression over the last 70 years,
with high rates of affective disorders among relatives and a younger age of onset in
successive cohorts.
In 2010, the Centers for Disease Control and Prevention (CDC) released a report
estimating the prevalence of current depression in adults from 2006-2008. Of
235,067 adults, 9% met the criteria for current depression, including 3.4% who met
the criteria for major depression.[46]
International statistics
Internationally reported adult prevalence rates of depression generally mirror those
of the United States, and estimates of 1-month prevalence of depression in
community-dwelling elderly are relatively consistent (eg, England, 2.9%; The
Netherlands, 2.0%; Sweden, 5.6%; Nigeria, 1.6%). However, sparse data are
available on the international incidence of major depression in children and
adolescents.
Helgason examined the entire Icelandic birth cohort of 1895-97 with periodic followup until cohort individuals reached age 74-76 years. The lifetime estimates of risk for
any affective disorder were 14.8% for females and 9.8% for males.[47] The
WorldHealthOrganization(WHO) collaborative study on the assessment of
depressive disorders found considerable similarity in depressive symptomatology
across cultures in Canada, Iran, Japan, and Switzerland.[48]
The Stirling County Study, which began shortly after World War II, offered a 40-year
perspective of the prevalence and incidence of psychiatric disorders in an adult
population in Atlantic Canada, in which the overall prevalence of depression
remained stable at 5% across 3 separate samples in 1952, 1970, and 1992. In the
2000 sample, however, the prevalence had shifted from older to younger persons,
and the female-to-male ratio had increased.[49]
Copeland et al found widely ranging prevalences for depression in elderly persons in
9 European populations. The prevalence for females was higher than that for males,
and there was no constant association between prevalence and age. Meta-analysis
revealed an overall prevalence of 12.3% and frequencies of 14.1% for females and
8.6% for males.[50]
Children and adolescents

The incidence of depression was 0.9% in preschool-aged children, 1.9% in schoolaged children, and 4.7% in adolescents in a study by Kashani and Sherman.[51] In
another study, more than 22% of female high school students and more than 11% of
male high school students reported 1 current or lifetime episode of unipolar
depression. The percentage of male students with 2 or more episodes of unipolar
depression was 4.9%; it was 1.6% in female students.[52]
Garrison et al reported a 1-year incidence of major depression of 3.3% in
adolescents aged 11-16 years.[53] Their epidemiologic study was conducted between
1987 and 1989 in a single school district in the southeastern United States.
In prepubertal children, boys and girls are affected equally. Hankin et al found that
the most critical time for sex differences in depression to emerge is from age 15-18
years.[54] During this period, the increase in overall rates of depression and onset of
new cases of depression peak.
Hispanic youths in Los Angeles county (aged 12-17 years) reported more symptoms
of depression, independent of socioeconomic status, when compared with white,
black, or Asian American adolescents, using the Children's Depression Inventory
(CDI).[55] This study also found significant effects of social class on depression. As
income decreased, the average prevalence of depression increased.
Elderly persons
Although rates of depression in women and men are highest in those aged 25-44
years, the incidence of clinically significant depressive symptoms increases with
advancing age, especially when associated with medical illness or
institutionalization. However, the depression might not meet criteria for major
depression because of somewhat atypical features of depression in elderly persons.
For instance, there is a higher prevalence of dysthymic disorder in aging and
medically ill populations.
Prognosis
Major depressive disorder has significant potential morbidity and mortality,
contributing as it does to suicide, incidence and adverse outcomes of medical
illness, disruption in interpersonal relationships, substance abuse, and lost work
time. With appropriate treatment, 70-80% of individuals with major depressive
disorder can achieve a significant reduction in symptoms, although as many as 50%
of patients may not respond to the initial treatment trial.
Twenty percent of individuals with major depressive disorder untreated at 1 year will
continue to meet criteria for the diagnosis, whereas an additional 40% will have a
partial remission. Pretreatment irritability and psychotic symptoms may be
associated with poorer outcomes. Partial remission and/or a history of prior chronic
major depressive episodes are risk factors for recurrent episodes and treatment
resistance.
A study of first-episode psychotic depression by Tohen et al found that most patients
achieved syndromal remission (86%) and recovery (84%); however, only 35%
recovered functionally. Earlier syndromal recovery was associated with subacute
onset, lower initial depression scores, and lack of mood-incongruent psychotic
features. Within 2 years, almost half the patients experienced new episodes. In 41%
of patients, the diagnosis was changed, usually to bipolar or schizoaffective
disorders.[56]
Recurrence of early depression

According to the AmericanAcademyofChildandAdolescentPsychiatry(AACAP)
practice parameters for depressive disorders in childhood and adolescence, a
history of a previous depressive episode, subsyndromal symptoms of depression,
dysthymia, and anxiety disorders increase the risk for future depression.[57] In a study
of an epidemiologic sample of 776 adolescents by Pine and associates, symptoms
of majordepressioninadolescencestrongly predicted episodes of major depression in
adulthood.[58]
Late-onset depression
The prognosis for patients with late-onset depression is felt to be poorer than that for
younger patients, and it appears to be dependent on physical disability or illness and
lack of social support. Of particular importance is the increasing risk of death by
suicide, particularly among elderly men. The length of a depressive episode in the
aging population is approximately 18 months, whereas in people 2055 years of
age, the length of an episode is 18 to 24 weeks.
In older patients, depression is frequently comorbid with chronic medical conditions
and can lead to worsening medical outcomes, including mortality.[26] For example,
coronary artery disease is a risk factor for the development of depression, and
depression is an independent risk factor for the development of coronary disease.
Patients with both conditions are more likely to die than those with coronary artery
disease alone. Both behavioral and physiologic explanations are likely for these
associations.[59]
Millard suggested the "rule of thirds" concerning the prognosis of late-onset
depression, which states that regardless of treatment, approximately one third of
patients will manifest remission, another one third will remain symptomatic in the
same condition, and the remaining one third will worsen.[60] In fact, research has
shown that approximately 60% of patients with late-onset depression will have at
least 1 recurrence, and up to 40% of these patients will have chronic or continuously
recurrent depression.[61]
Late-onset depression has been reported to double the risk of developing
mildcognitiveimpairment[62] and the likelihood that the mild impairment will develop
into dementia.[63] The Diabetes and Aging Study showed that when depression is
comorbid with type 2 diabetes, it increases the risk of all-cause dementia by about
2-fold compared with diabetes alone.[64] A 40-month study of 2977 middle-aged and
older adults with long-standing type 2 diabetes found depression at baseline to be
associated with accelerated cognitive decline.[65, 66]
Compared with participants without a depression history, those with late-life
depression reportedly have increased all-cause dementia risk; however, early-life
depression had no association with dementia risk.[67] Treating depression has been
suggested to possibly stunt progression to mild cognitive impairment and then to
dementia, although there has been little evaluation of this hypothesis to date.
Suicide
Depression plays a role in more than one half of all suicide attempts, whereas the
lifetime risk of suicide among patients with untreated depressive disorder is nearly
20%.[68] According to Centers for Disease Control and Prevention (CDC) data,
suicide was the 10th leading cause of death in the United States in 2009, accounting
for 36,909 deaths; it was the second leading cause of death in people 25-34 years of
age, the third leading cause in people aged 10-24 years, and the fourth leading
cause at ages 35-54.[69]
However, despite these data and the fact that depression is more often diagnosed in
women, the highest suicide rate is in men older than 75 years (see the graph below);
more men than women die from suicide by a factor of 4.5:1. White men complete
more than 78% of all suicides, and 56% of suicide deaths in males involve firearms.
Poisoning is the predominant method among females. Attempted suicide is more
frequent in women.
From 1991-2006, the suicide rate was consistently higher among males. Suicide rates
declined among both sexes from 1991-2000; the rate among males decreased from 24.64 to
20.67 suicides per 100,000 and 5.48 to 4.62 suicides per 100,000 among females. From
2000-2006, however, the suicide rates gradually increased among females. Note: All rates are
age-adjusted to the standard 2000 population. Rates based on less than 20 deaths are
statistically unreliable. Source: Centers for Disease Control and Prevention. National suicide
statistics at a glance: Trends in suicide rates among persons ages 10 years and older, by sex,
United States, 1991-2006. Available at:
http://www.cdc.gov/violenceprevention/suicide/statistics/trends01.html. Accessed: May 5,
2010.
In addition to older age and male sex, risk factors for suicide include the following[70,
71]
:
Diagnosis of major depression

Previous history of suicide attempts
Depressive symptoms with agitation or distress
Burden of medical disease and the presence of a current serious medical
condition (although this risk may be mediated by a diagnosis of depression)
Recent stressful life events, especially family discord
Lack of social support
Being widowed or divorced
The presence of a gun in the home
Unexplained weight loss
High levels of anxiety
Lack of a reason not to commit suicide
Presence of a specific plan that can be carried out
Rehearsal of the plan
The relationship between use of antidepressants and risk of suicide varies with
patient age. Treatment with antidepressants has been associated with increased
suicidality in children, adolescents, and young adults 18 to 24 years of age. There is
no evidence of increased risk for adults older than 24 years of age; for adults 65
years of age or older, the risk is actually decreased.[72]
Suicide rates among Native Americans and Alaskan Natives between ages 15 and
34 years are almost twice the national average for this age range. Hispanic females
make significantly more suicide attempts than their male or non-Hispanic
counterparts.
In one study, there were strong correlations of suicide rates with indicators of access
to health care in the United States.[73] Multivariate analysis of state-by-state statistics
showed that the state rate of federal aid for mental health was the strongest
indicator, followed by the rate of uninsured persons and population density of
psychiatrists and physicians and by population density. These researchers
concluded that the findings support the view that clinical intervention is a crucial
element in the prevention of suicide.
In 2005, 1.4% of all deaths worldwide were attributed to suicide. The actual number
is unknown, as underreporting is predictably significant in many regions of the world.
Suicide is estimated to be the eighth leading cause of death in all age ranges. In
Eastern Europe, 10 countries report more than 27 suicides per 100,000 persons.
Latin America and Muslim countries report the lowest rates, with fewer than 6.5 cases per
100,000 persons. Suicide rates increased from 1955-2009 in most countries but have decreased
from 1990-2009.
10
Depression Treatment & Management: Approach Considerations, Pharmacologic The...
Depression Treatment & Management

Approach Considerations
A wide range of effective treatments is available for major depressive disorder.
Medication alone (see Medication) and brief psychotherapy (e.g., cognitivebehavioral therapy, interpersonal therapy) alone can relieve depressive symptoms.
There is also empirical support for the ability of brief psychotherapy (CBT) to prevent
relapse.
In children and adolescents, however, pharmacotherapy by itself is insufficient
treatment. Moreover, in all patient populations, the combination of medication and
psychotherapy generally provides the quickest and most sustained response.
Combination therapy has also been associated with significantly higher rates of
improvement in depressive symptoms; increased quality of life; and better treatment
compliance, especially when treatment is needed for longer than 3 months.[2, 3]
Medications
Usually, 2-12 weeks at a therapeutic dose, with assumed adherence to the regimen,
are needed for a clinical response to become evident. The choice of medication
should be guided by anticipated safety and tolerability, which aid in compliance;
physician familiarity, which aids in patient education and anticipation of adverse
effects; and history of previous treatments. Often, treatment failures are caused by
medication noncompliance, inadequate duration of therapy, or inadequate dosing.
According to the 2008 American College of Physicians (ACP) guideline (the most
recent release of the guideline) on using second-generation antidepressants to treat
depressive disorders, patient preferences should be given serious consideration
when choosing the best course of pharmacotherapy for patients with depressive
disorders. The patient may want to avoid use of a particular antidepressant if he or
she had a previous negative experience with the drug.[97]
The 2008 ACP guideline advises that treatment for major depressive disorder should
be altered if the patient does not have an adequate response to pharmacotherapy
within 6-8 weeks. Once satisfactory response is achieved, treatment should be
continued for 4-9 months in patients with a first episode of major depression that was
not associated with significant suicidality or catastrophic outcomes. In those who
have had 2 or more episodes of depression, a longer course of maintenance
treatment may prove beneficial.[97]
In 2011, the American Psychiatric Association (APA) updated its Practice Guideline
for the Treatment of Patients with Major Depressive Disorder.[6] The 2011 APA
guideline emphasizes the need to customize a treatment plan for each patient based
on a careful assessment of symptoms, including rating scale measurements
administered by a clinician or the patient, as well as an analysis of therapeutic
benefits and side effects.
Treatment should maximize patient function within specific and realistic goals. The
initial modality should be chosen on the basis of the following[6] :
Clinical assessment
Presence of other disorders
Stressors
Patient preference
Reactions to previous treatment
Psychotherapy
Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute
sessions. Although there is wide variation in practice, psychotherapy tends to be
time-limited (e.g., 16 sessions).
In the 1990s, The American Psychological Associations Division 12 Task Force on
Promotion and Dissemination of Psychological Procedures[98, 99] developed criteria
for evaluating the empirical support for psychological treatments. Chambless and
Hollon[100] refined these guidelines such that a therapy is considered efficacious and
specific if there is evidence from high-quality studies in two or more settings
indicating that it is superior to a pill or psychological placebo or to another bonafide
treatment. A treatment is considered efficacious if there is evidence from two or
more settings that it is superior to no treatment. A therapy is considered to be
possibly efficacious if there is research support from one or more studies in a single
setting. It is recommended that individuals seeking psychotherapy for depression
receive one with empirical support (see below).
Pharmacologic Therapy for Depression

Drugs used for treatment of depression include the following:

Serotonin-Dopamine Activity Modulators (SDAMs)
St. John's wort
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Selective serotonin reuptake inhibitors

SSRIs include the following:
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
Vilazodone (Viibryd)
Vortioxetine (Brintellix)
SSRIs have the advantage of ease of dosing and low toxicity in overdose. SSRIs are
greatly preferred over the other classes of antidepressants for the treatment of
children and adolescents, and they are also the first-line medications for late-onset
depression. This recommendation is supported by the 2011 APA guideline.[6]
The adverse-effect profile of SSRIs is less prominent than that of some other agents,
which promotes better compliance. Common adverse effects include gastrointestinal
upset, sexual dysfunction, and changes in energy level (ie, fatigue, restlessness).
The SSRIs are thought to be relatively unproblematic in patients with cardiac
disease, as these agents do not appear to affect blood pressure, heart rate, cardiac
conduction, or cardiac rhythm. However, dose-dependent QT prolongation has been
reported with citalopram.
Consequently, the US Food and Drug Administration (FDA) has advised that
citalopram is not recommended in patients with congenital long QT syndrome.[101]
Use of citalopram may be appropriate for patients with this condition who lack viable
alternatives; however, in such cases, the drug should be given at a low dose, and
electrocardiographic and/or electrolyte monitoring should be performed. Citalopram
should be discontinued in patients who are found to have a persistent corrected QT
interval (QTc) greater than 500 ms.
The dose of citalopram should not exceed 40 mg/day, because of the risk of
potentially fatal cardiac arrhythmias; furthermore, higher doses have not been shown
to be more effective in treating depression. For patients older than 60 years, the
maximum recommended dose of citalopram is 20 mg/day.[101, 102]
In September 2013, the FDA approved vortioxetine (Brintellix) for the treatment of
major depressive disorder in adults. The drugs mechanism of action involves
enhancement of serotonergic activity through 5-HT reuptake inhibition. It also
modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3
receptor antagonism, although the contribution of these activities to the
antidepressant effect is not fully understood.
Approval was based on 5 short-term (6-8 week) studies,[103, 104, 105, 106, 107] including
one that focused on elderly adults.[107] These studies demonstrated a statistically
significant reduction in overall symptoms of depression with vortioxetine compared to
placebo, with most consistent results obtained within a dosage range of 15-20
mg/day. Also, a long-term (24-64 week) maintenance study showed a significantly
longer time to relapse with vortioxetine compared to placebo.[108, 109] Two studies
using lower doses (2.5-5 mg/day) showed no significant difference in efficacy
between the drug and placebo.[110, 111] The most common adverse effects were
nausea, diarrhea, dry mouth, constipation, vomiting, dizziness, and sexual
dysfunction.
Serotonin/norepinephrine reuptake inhibitors

SNRIs, which include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine
(Cymbalta), and levomilnacipran (Fetzima) can be used as first-line agents,
particularly in patients with significant fatigue or pain syndromes associated with the
episode of depression. SNRIs also have an important role as second-line agents in
patients who have not responded to SSRIs.
The concurrent use of SNRIs with other antidepressants may be more problematic.
For example, the Combining Medications to Enhance Depression Outcomes (COMED) study found that the combination of extended-release venlafaxine plus
mirtazapine may actually pose a greater risk of adverse events and does not
outperform monotherapy.[112]
The safety, tolerability, and side-effect profiles of SNRIs include those of the SSRIs,
as well as noradrenergic side effects, such as hypertension.
In July 2013, the FDA approved the newest SNRI levomilnacipram (Fetzima) which
is available as a once-daily sustained-release formulation. It has greater potency for
norepinephrine reuptake inhibition than for serotonin reuptake inhibition without
directly affecting the uptake of dopamine or other neurotransmitters.
Atypical antidepressants include bupropion (Wellbutrin), mirtazapine (Remeron),
nefazodone, and trazodone (Desyrel). They have all been found to be effective in
monotherapy in major depressive disorder and may be used in combination therapy
for more difficult to treat depression.
Nevertheless, this group also shows low toxicity in overdose. In addition, bupropion
has the advantage over the SSRIs of causing less sexual dysfunction and less GI
distress. Mirtazapine is associated with a high risk of weight gain, so patients who
are treated with this agent should have careful monitoring of weight.
Serotonin-Dopamine Activity Modulators

SDAMs include brexpiprazole (Rexulti) and aripiprazole (Abilify). SDAMs act as a
partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an
antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. This mechanism of
action is unique from other atypical antipsychotic drugs.
Brexpiprazole is indicated as adjunctive therapy for major depressive disorder
(MDD). Aripiprazole is indicated for schizophrenia, acute treatment of manic and
12
mixed episodes associated with bipolar I, as an adjunct to MDD, irritability

associated with autistic disorder, and treatment of Tourette disorder. Also,
aripiprazole prompt-acting injection is indicated for agitation associated with
schizophrenia or bipolar mania.
In clinical trials, brexpiprazole was added to existing antidepressant therapy in
patients who had failed multiple trials of antidepressant therapy. Patients enrolled
met DSM-IV-TR criteria for MDD. Brexpiprazole (2 mg and 3 mg daily) plus
antidepressant therapy was superior to placebo plus antidepressant therapy on the
primary endpoint (ie, change in Montgomery-sberg Depression Rating Scale
scores).[113]
Tricyclic antidepressants
TCAs include the following:
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Desipramine (Norpramin)
Doxepin (Sinequan)
Imipramine (Tofranil)
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Trimipramine (Surmontil)
TCAs have a long record of efficacy in the treatment of depression. They are used
less commonly because of their side-effect profile and their considerable toxicity in
overdose (see AntidepressantToxicity).
Monoamine oxidase inhibitors

MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam),
and tranylcypromine (Parnate). These agents are widely effective in a broad range of
affective and anxiety disorders. Because of the risk of hypertensive crisis, patients
on these medications must follow a low-tyramine diet. Other adverse effects can
include insomnia, anxiety, orthostasis, weight gain, and sexual dysfunction.
St. John's wort

St. John's wort (Hypericum perforatum) is an herbal remedy available over the
counter. Although St. John's wort is considered a first-line antidepressant in many
European countries, it has only recently gained popularity in the United States. Uses
include treatment of mild to moderate depressive symptoms, but of note, it has not
been shown to be effective in major depressive episodes and cannot be
recommended as a first-line treatment in moderate depression.
St. Johns wort may act as an SSRI. The common dosage is 300 mg 3 times a day
with meals to prevent GI upset. If no clinical response occurs after 3-6 months,
encouraging the use of another medication is recommended.
In addressing the issue of alternative therapies for depression, the 2011 APA
guideline noted that St. John's wort might be considered, but evidence for its
effectiveness is modest, and more information is needed about its interaction with
other drugs.[6]
Comparative effectiveness of antidepressants

The AgencyforHealthcare Research andQuality (AHRQ) compared the effectiveness
of the following 12 second-generation antidepressants[114] :
Bupropion
Citalopram
Duloxetine
Escitalopram
Fluoxetine
Fluvoxamine
Mirtazapine
Paroxetine
Sertraline
Trazodone
Venlafaxine
The AHRQ found that average effectiveness of those 12 antidepressants appeared

similar, but the studies reviewed were not designed to test variation among patients
responses to individual drugs. However, the AHRQ did find moderately strong
evidence of differences among individual second-generation antidepressants with
respect to onset of action and some measures (eg, sexual functioning) that could
affect health-related quality of life.
The 2008 ACP guideline advises clinicians to choose second-generation
antidepressants on the basis of adverse effects, cost, and patient preferences, since
all these agents have comparable efficacy. Patient status, response to therapy, and
adverse effects of antidepressants should be assessed within 1-2 weeks of starting
therapy.[97]
Zisook et al found that among depressed patients with suicidal ideation at baseline,
the combination of sustained-release bupropion and escitalopram was more
effective at reducing suicidal ideation than sustained-release venlafaxine plus
mirtazapine; the former was most effective at week 12 of treatment. In this study, of
665 outpatients with nonpsychotic chronic and/or recurrent major depressive
disorder, 4 patients attempted suicide; all were receiving venlafaxine plus
mirtazapine.[115]
Antidepressant effectiveness and depression severity

In a meta-analysis, Fournier et al found that medication superiority over placebo
increased with increases in baseline depression severity, crossing the threshold for a
clinically significant difference at a baseline Hamilton Depression Rating Scale
(HDRS) score of 25.[116] In patients with mild or moderate depression, antidepressant medication
had minimal or no benefit compared with placebo, but in patients with very severe depressio,
antidepressant drugs provided a substantial benefit compared with placebo.
13
Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...
Depression Medication
Medication Summary
Drugs used for the treatment of depression include the following:

Serotonin-Dopamine Activity Modulator (SDAMs)
St. Johns wort ( Hypericum perforatum)
All antidepressants on the market are potentially effective. Usually, 2-6 weeks at a
therapeutic-dose level are needed to observe a clinical response. The choice of
medication should be guided by anticipated safety and tolerability, which aid in
compliance; physician familiarity, which aids in patient education and anticipation of
adverse effects; and history of previous treatments. Often, treatment failures are
caused not by clinical resistance but by medication noncompliance, inadequate
duration of therapy, or inadequate dosing.
Antidepressants can have central and peripheral anticholinergic effects, as well as
sedative effects, and can block the active reuptake of norepinephrine (NE), serotonin
(5-HT), and dopamine. SSRIs are metabolized via the cytochrome P-450 system
and may have drug interactions on that basis. The degree of enzyme inhibition
varies among SSRIs. Effects on blood levels and bioavailability of coadministered
drugs, as well as pharmacodynamic interactions, account for most clinically
significant SSRI-drug interactions.
All available antidepressants appear to work via one or more of the following
mechanisms[129] :
Presynaptic inhibition of uptake of 5-HT or NE
Antagonist activity at presynaptic inhibitory 5-HT or NE receptor sites, thereby
enhancing neurotransmitter release
Antagonism of NE beta or serotonin 5-HT2 receptors
N-Methyl-D-aspartate (NMDA) receptor antagonism
Induction of brain-derived neurotrophic factor (BDNF)
Inhibition of monoamine oxidase, thereby reducing neurotransmitter
breakdown
Antidepressants, SSRIs
Class Summary
SSRIs are the initial antidepressants of choice for uncomplicated depression
because of their minimal anticholinergic effects.
They have the advantage of ease of dosing and low toxicity in overdose. SSRIs are
greatly preferred over the other classes of antidepressants for the treatment of
children and adolescents, and these agents are also the first-line medications for
late-onset depression, due to their superior tolerability and comparatively more
benign safety profile.
The SSRIs are not thought to be as worrisome in patients with cardiac disease, as
they do not appear to exert any effect on blood pressure, heart rate, cardiac
conduction, or cardiac rhythm; however, dose-dependent QT prolongation has been
reported with citalopram. Because of the risk for QT prolongation, citalopram is
contraindicated in individuals with congenital long QT syndrome.[101, 102]
Because the adverse-effect profile of SSRIs is less prominent than other agents,
improved compliance is promoted. Common adverse effects of SSRIs include
gastrointestinal upset, sexual dysfunction, bleeding, emotional blunting, cognitive
dysfunction, and changes in energy level (ie, fatigue, restlessness).
The US Food and Drug Administration issued a safety information update in
December 2011 concluding that it is unclear whether the use of SSRIs during
pregnancy causes persistent pulmonary hypertension in the newborn. The FDA
currently recommends that health care professionals and patients weigh the small
potential risk of persistent pulmonary hypertension against the substantial risks of
untreated depression during pregnancy.[101]
View full drug information
Citalopram (Celexa)
Citalopram enhances serotonin activity as a result of selective reuptake inhibition at
the presynaptic neuronal membrane. It has minimal effects on norepinephrine and
dopamine.
Although it has FDA approval only for depression, citalopram is commonly
prescribed for other psychiatric disorders, including obsessive-compulsive disorder,
generalized anxiety disorder, panic disorder, and premenstrual dysphoric disorder.
The FDA advises that the dose of citalopram not exceed 40 mg/day because of the
risk of potentially fatal QT prolongation. Furthermore, higher doses have not been
shown to be more effective in treating depression.[101]
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Escitalopram (Lexapro)
Escitalopram is an SSRI and S-enantiomer of citalopram used for the treatment of
depression. The mechanism of action is thought to be potentiation of serotonergic
activity in the central nervous system resulting from inhibition of CNS neuronal
reuptake of serotonin. Escitalopram has little or no effect on norepinephrine and
dopamine reuptake.
Onset of depression relief may occur after 1-2 wk, but individual responses vary, and
a full effect may not be seen until 8-12 weeks.
Fluoxetine (Prozac)
Fluoxetine is a commonly used SSRI and was the first of the SSRIs to become
available in the United States. It selectively inhibits presynaptic serotonin reuptake
with minimal or no effect on reuptake of norepinephrine or dopamine. It is commonly
prescribed for many indications that are not FDA approved, including fibromyalgia,
posttraumatic stress disorder, Raynaud phenomenon, social anxiety disorder, and
selective mutism.
Fluvoxamine (Luvox)
Fluvoxamine enhances serotonin activity due to selective reuptake inhibition at the
neuronal membrane. It does not significantly bind to alpha-adrenergic, histamine, or
cholinergic receptors and thus has fewer side effects than tricyclic antidepressants.
Fluvoxamine is a strong inhibitor of cytochrome P-450. Although fluvoxamine is FDA
approved only for obsessive-compulsive disorder, it is commonly prescribed for other
psychiatric disorders, including social anxiety disorder, posttraumatic stress disorder,
pain disorder, and major depression.
Paroxetine (Paxil)
Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake and also has
a weak effect on norepinephrine and dopamine neuronal reuptake. It has slight
anticholinergic effects and may cause more weight gain than other SSRIs.
Paroxetine is sometimes prescribed for indications that are not FDA approved, such
as eating disorders and the relief of vasomotor symptoms of menopause.
Sertraline (Zoloft)
Sertraline selectively inhibits presynaptic serotonin reuptake. It has very minimal
effects on norepinephrine and dopamine neuronal uptake. Sertraline is sometimes
prescribed for indications that are not FDA approved, such as eating disorders,
generalized anxiety disorder, and panic disorder.
Vilazodone (Viibryd)
Vilazodone's mechanism of antidepressant effect is related to serotonergic activity in
the CNS through selective inhibition of serotonin reuptake. This agent is also a
partial agonist at serotonergic 5-HT1A receptors, although the contribution of this
activity to the drug's antidepressant effect is unknown.
Vilazodone is indicated for major depressive disorder. The dose should be adjusted
when this agent is given with moderate or strong CYP3A4 inhibitors.
Vortioxetine (Brintellix)
Vortioxetine enhances serotonergic activity through 5-HT reuptake inhibition. It also
modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3
receptor antagonism, although the contribution of these activities to the
antidepressant effect is not fully understood. It is approved to treat major depressive
disorder in adults.
Antidepressants, SNRIs
Class Summary
SNRIs can be used as first-line agents, particularly in patients with significant fatigue
or pain syndromes associated with the episode of depression. The SNRIs also have
an important role as second-line agents in patients who have not responded to
SSRIs. Safety, tolerability, and side-effect profiles are similar to those of the SSRIs,
with the exception that venlafaxine and desvenlafaxine have been associated
(rarely) with a sustained rise in blood pressure. Venlafaxine has been particularly
associated with hyponatremia.
Desvenlafaxine (Pristiq)
Desvenlafaxine is an SNRI that is indicated for the treatment of major depressive
disorder.
Duloxetine (Cymbalta)
15
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine uptake, and

antidepressant action is thought to be due to serotonergic and noradrenergic
potentiation in the central nervous system.
Venlafaxine (Effexor, Effexor XR)

Venlafaxine and its active metabolite inhibit neuronal serotonin and norepinephrine
reuptake. They are weak inhibitors of dopamine reuptake. In addition, it causes betareceptor down-regulation. Venlafaxine is sometimes prescribed for nonFDAapproved indications, such as obsessive-compulsive disorder, hot flashes,
neuropathic pain, attention-deficit/hyperactivity disorder, and posttraumatic stress
disorder.
Levomilnacipran (Fetzima)
Levomilnacipran is the active enantiomer milnacipran and should be administered
once daily. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake,
and inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro
than serotonin without directly affecting the uptake of dopamine or other
neurotransmitters.
Antidepressants, TCAs
Class Summary
TCAs have a long record of efficacy in the treatment of depression and have the
advantage of lower cost. They are used less commonly because of the need to
titrate the dose to a therapeutic level and because of their considerable toxicity in
overdose. TCAs are often prescribed for many other psychiatric disorders, such as
generalized anxiety disorder and posttraumatic stress disorder. They are also used
to treat chronic pain, such as neuropathy, and migraine headaches.
Amitriptyline (Elavil)
Amitriptyline inhibits the reuptake of norepinephrine and, more potently, serotonin at
the presynaptic neuronal membrane, which increases concentration in the CNS. It
has a high affinity for histamine H1 and muscarinic M1 receptors. Amitriptyline can
cause weight gain, sedation, and anticholinergic side effects. It is often used for non
FDA-approved indications, such as chronic pain management, diabetic neuropathy,
migraine prophylaxis, and posttraumatic stress disorder.
Desipramine (Norpramin)
Desipramine inhibits the reuptake of serotonin and, more potently, norepinephrine at
the presynaptic neuronal membrane. It is a commonly used TCA that is relatively
less sedating and tends to have fewer anticholinergic and antihistaminic adverse
effects than other TCAs. It is sometimes used for off-label indications such as
peripheral neuropathy and attention-deficit/hyperactivity disorder.
Imipramine (Tofranil)
Imipramine is one of the oldest agents available for the treatment of depression. It is
demethylated in the liver to desipramine. Imipramine inhibits the reuptake of
norepinephrine and, more potently, serotonin at the presynaptic neuronal
membrane. It has a strong affinity for alpha-adrenergic, H1, and M1 receptors.
Common side effects include orthostasis, sedation, weight gain, and anticholinergic
effects. It is also used off-label in the treatment of panic disorder, posttraumatic
stress disorder, and attention deficit/hyperactivity disorder.
Clomipramine (Anafranil)
Clomipramine potently inhibits the reuptake of serotonin at the presynaptic neuronal
membrane. It has strong affinities to both H1 and M1 receptors, which results in
sedation, weight gain, and anticholinergic side effects. Although clomipramine is
FDA approved only for obsessive-compulsive disorder, it has also been prescribed
for depression, panic attacks, and chronic pain.
Nortriptyline (Pamelor)
Nortriptyline blocks the reuptake of serotonin and, more potently, norepinephrine at
the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and,
thus, is better tolerated than other TCAs. Although nortriptyline is FDA approved only
for depression, it has also been prescribed for chronic pain, myofascial pain, anxiety
disorders, and attention-deficit/hyperactivity disorder. As with desipramine, there is a
therapeutic window for nortriptyline
Protriptyline (Vivactil)
Protriptyline increases the synaptic concentration of norepinephrine in the CNS by
inhibiting reuptake at the presynaptic neuronal membrane. It has less affinity for H1
and M1 receptors and, thus, is better tolerated than tertiary amine TCAs.
16
Doxepin (Sinequan, Silenor)

Doxepin increases the concentration of serotonin and norepinephrine in the CNS by
inhibiting their reuptake at the presynaptic neuronal membrane. These effects are
associated with a decrease in the symptoms of depression. It has the highest affinity
for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.
Trimipramine (Surmontil)
Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic
neuron and elicits strong anticholinergic effects. It has a high affinity for the H1
receptor and is thus very sedating, but it is useful for gastroesophageal reflux.
Amoxapine
Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at
the presynaptic neuron. It also blocks dopamine receptors, causing it to have
antipsychotic activity, as well.
Antidepressants, MAO Inhibitors

Class Summary
Monoamine oxidase inhibitors were the first antidepressants discovered, in the early
1950s. They are widely effective in a broad range of affective and anxiety disorders.
MAOIs irreversibly block monamine oxidase, which has 2 forms, including MOAa and
MOAb. MAOa breaks down serotonin and norepinephrine. MOAb metabolizes
phenylethylamine. Both forms break down dopamine.
MOAIs are not considered first-line treatment for depression because of the side
effects, drug-drug interactions, and dietary restrictions. Common side effects include
hypotension, dizziness, dry mouth, gastrointestinal upset, urinary hesitancy,
headache and myoclonic jerks. Because of the risk of hypertensive crisis with drugs
that specifically inhibit MAOa in the gastrointestinal tract, patients on these
medications must follow a low-tyramine diet.
Selegiline transdermal patch (Emsam)

Selegiline inhibits MAOb at lower doses and both forms at higher doses. Because it
does not inhibit MAOa, it does not require dietary restrictions at lower doses. Lower
doses of oral selegiline (Eldepryl) appear to lack antidepressant properties and are
usually prescribed to treat Parkinson disease. Higher doses are used to treat major
depressive disorder, and the selegiline transdermal patch is FDA approved for this
indication. Selegiline is sometimes used off-label to treat attentiondeficit/hyperactivity disorder.
Dietary restrictions are not required for the 6 mg/24 hour patch because there is no
risk of hypertensive crisis with this dose, given the lack of MAOa inhibition. Higher
doses require dietary restrictions. The patch may be beneficial to those that cannot
take oral medications. To avoid serotonin syndrome, initiating and stopping
selegiline must be handled carefully.
Tranylcypromine (Parnate)
Tranylcypromine is used to treat major depression. It binds irreversibly to MAOa and
to a lesser extent to MAOb, thereby reducing monoamine breakdown and enhancing
synaptic availability. Clinical effects are not normally seen for 2-4 weeks. It has
similar side effects as other MAOIs, but it is more likely to cause insomnia.
Phenelzine (Nardil)
Phenelzine is used to treat depression. It irreversibly inhibits both MOAa and MOAb.
Side effects are similar to those of other MAOIs, but anticholinergic side effects are
more common. Phenelzine causes less insomnia than tranylcypromine but is more
likely to cause sedation, weight gain, and sexual dysfunction.
Isocarboxazid (Marplan)
Isocarboxazid is a nonselective hydrazine MAOI that is indicated for the treatment of
depression. The mechanism by which MAOIs act as an antidepressant is not fully
understood, but it is thought to be that these drugs increase the CNS concentrations
of norepinephrine, dopamine, and serotonin.
Augmenting Agents
Class Summary
Augmentation is a common strategy for treatment-resistant depression. It consists of
adding a medication with a different mechanism of action to the therapeutic regimen.
Lithium carbonate (Eskalith, Lithane, Lithobid)

Lithium carbonate can be used as an effective augmenting agent in combination with
an antidepressant in cases of treatment-resistant depression. It can also be used to
17
treat or prevent episodes of depression. Lithium is contraindicated in patients with

significant renal impairment.
It is important to note that lithium interacts with many drugs. Use of lithium often
requires monitoring of lithium levels and renal and thyroid function tests.
Buspirone (BuSpar)
Buspirone is marketed as an antianxiety medication; however, it may have
antidepressant effects at doses above 45 mg/day. The antidepressant effects may
increase when buspirone is used in combination with SSRIs and TCAs in patients
with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with
serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but
may take up to 2-3 weeks for full efficacy.
Serotonin-Dopamine Activity Modulators

Class Summary
Serotonin-dopamine activity modulators (SDAMs) act as a partial agonist at 5-HT1A
and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and
noradrenaline alpha1B/2C receptors. This mechanism of action is unique from other
atypical antipsychotic drugs.
Brexpiprazole (Rexulti)
Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for
major depressive disorder. Dosage modifications are necessary with renal or hepatic
impairment. Dosage modifications are also needed for individuals who are poor
metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or
CYP3A4.
Aripiprazole (Abilify, Abilify Discmelt)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for
major depressive disorder. Dosage modifications are also needed for individuals
who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism
by CYP2D6 or CYP3A4. No dosage adjustment is required for renal or hepatic
impairment.
Antidepressants, Other
Class Summary
Atypical antidepressants include bupropion (Wellbutrin, Wellbutrin SR), mirtazapine
(Remeron), and trazodone (Desyrel). These agents are effective in treating major
depression and may be effective in combination therapy in major depressive
disorder. This group also shows low toxicity in overdose. Wellbutrin SR may have an
advantage over the SSRIs by causing less sexual dysfunction and weight gain.
Bupropion (Wellbutrin)
Bupropion inhibits neuronal dopamine reuptake and decreases the rate of
norepinephrine activity. In addition to major depressive disorder, the indications for
bupropion include smoking cessation. Off-label indications include attentiondeficit/hyperactivity disorder and depression associated with bipolar disorder.
Common side effects include headache and mild weight loss. Unlike other
antidepressants, bupropion does not cause sexual dysfunction.
Mirtazapine (Remeron, Remeron SolTab)

Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low
affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3.
Common side effects include sedation, weight gain, and dry mouth.
Trazodone (Desyrel, Oleptro)

Trazodone is effective in the treatment of major depression. It inhibits reuptake of
serotonin and modulates serotonergic neurotransmission. It also significantly blocks
histamine (H1) receptors. Its most common side effect is sedation, and thus, it has
an off-label indication as a hypnotic. It can be very rarely associated with priapism, a
medical emergency and a dangerous side effect of this drug in men. It is often used
at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.
Stimulants
Class Summary
The CNS stimulants dextroamphetamine (Dexedrine) and methylphenidate (Ritalin)
are sometimes used to augment antidepressants in patients with resistant
depression.
Dextroamphetamine (Dexedrine)
18
This is an augmenting agent in resistant depression. It has been studied most for
treating patients who are medically ill and depressed. It is available as a sustainedrelease preparation.
Methylphenidate (Ritalin)
Methylphenidate has been mostly studied for treating patients who are medically ill
and depressed. It is available as a sustained-release preparation.
Methylphenidate (Ritalin)
Methylphenidate has been mostly studied for treating patients who are medically ill
and depressed. It is available as a sustained-release preparation.
Thyroid Products
Class Summary
Thyroid hormones liothyronine (T3, Cytomel) may modulate the effect of
antidepressants.
Liothyronine (Liothyronine T3, Cytomel)

This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie,
nonresponders to antidepressants) to responders by increasing receptor sensitivity
and enhancing the effects of TCAs.
Neurology & Psychiatry, Herbals

Class Summary
Although St. John's wort is considered a first-line antidepressant in many European
countries, it has only recently gained popularity in the United States. Uses include
treatment of mild to moderate depressive symptoms, but efficacy has not been
demonstrated for major depression.
Hypericum perforatum (St John's Wort)

St John's wort is believed to act as an antidepressant by increasing concentrations
of CNS neurotransmitters, including serotonin. The common dosage is 300 mg 3
times a day with meals to prevent GI upset. If no clinical response occurs after 3-6
months, encouraging the use of another medication is essential.
19
Contributor Information and Disclosures

Author
Jerry L Halverson, MD Medical Director of Adult Services, Rogers Memorial Hospital; Voluntary Clinical Assistant
Professor, Department of Psychiatry, University of Wisconsin School of Medicine and Public Health; Clinical
Assistant Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical College of
Wisconsin
Jerry L Halverson, MD is a member of the following medical societies: American Medical Association, American
Psychiatric Association, American College of Psychiatrists
Disclosure: Nothing to disclose.
Coauthor(s)
Ravinder N Bhalla, MD Assistant Clinical Professor of Child Psychiatry, University of Medicine and Dentistry of
New Jersey; Medical Director, Mental Health Clinic of Passaic; Consulting Staff, Christian Health Care Center
Ravinder N Bhalla, MD is a member of the following medical societies: American Academy of Child and
Adolescent Psychiatry
Louise B Andrew, MD, JD Medical-Legal, Risk Management and Trial Consultant, Litigation Stress Counselor
Louise B Andrew, MD, JD is a member of the following medical societies: American Association of Women
Emergency Physicians, American College of Emergency Physicians, American Medical Association
Pascale Moraille-Bhalla, MD Medical Director, Outpatient Clinic of Hoboken University Medical Center; Staff
Psychiatrist, Mental Health Clinic of Passaic
Pascale Moraille-Bhalla, MD is a member of the following medical societies: American Psychiatric Association
Rachel C Leonard, PhD Behavioral Activation Specialist and Clinical Supervisor, OCD Center and CognitiveBehavioral Therapy Services, Rogers Memorial Hospital
Chief Editor
David Bienenfeld, MD Professor, Departments of Psychiatry and Geriatric Medicine, Wright State University,
Boonshoft School of Medicine
David Bienenfeld, MD is a member of the following medical societies: American Medical Association, American
Psychiatric Association, Association for Academic Psychiatry
26.04.2016
Medscape Reference
(www.medscape.com)
Bipolar affective disorder/

mood stabilizer
Overview
Treatment
Medication
Handout: Lecture Prof. Dr. Dr. Mller
20
Overview
Practice Essentials.22
Background......23
Pathophysiology..23
Etiology.....26
Epidemiology....27
Prognosis......28
Patient Education........28
Treatment
Approach Considerations...29
Indications for Inpatients Management........29
Considerations for Partial Hospitalization or Day Treatment....30
Considerations of Outpatient Treatment......30
Pharmacological Therapy......31
Medication
Medication Summary.....35
Anxiolytics, Benzodiazepines.......35
Mood stabilizer....35
Anticonvulsants......35
Antipsychotics, 2nd Generation.......36
Antipsychotics, 1st Generation....37
Antipsychotics, Phenothiazine.....37
Antiparkinson Agents, Dopamine Agonists....38
21
Bipolar Affective Disorder: Practice Essentials, Background, Pathophysiology
Bipolar Affective Disorder

Author: Stephen Soreff, MD; Chief Editor: Iqbal Ahmed, MBBS, FRCPsych(UK) more...
Updated: Feb 09, 2016
Practice Essentials
Bipolar affective disorder, or manic-depressive illness (MDI), is a common, severe,
and persistent mental illness. This condition is a serious lifelong struggle and
challenge.[1]
Signs and symptoms

Bipolar affective disorder is characterized by periods of deep, prolonged, and
profound depression that alternate with periods of an excessively elevated or irritable
mood known as mania.
Manic episodes are feature at least 1 week of profound mood disturbance,
characterized by elation, irritability, or expansiveness (referred to as gateway
criteria). At least 3 of the following symptoms must also be present[2] :
Grandiosity
Diminished need for sleep
Excessive talking or pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity at home, at work, or sexually
Excessive pleasurable activities, often with painful consequences
Hypomanic episodes are characterized by an elevated, expansive, or irritable mood

of at least 4 consecutive days duration. At least 3 of the following symptoms are
also present[2] :
Grandiosity or inflated self-esteem

Diminished need for sleep
Pressured speech
Racing thoughts or flight of ideas
Clear evidence of distractibility
Increased level of goal-focused activity at home, at work, or sexually
Engaging in activities with a high potential for painful consequences
Major depressive episodes are characterized as, for the same 2 weeks, the person
experiences 5 or more of the following symptoms, with at least 1 of the symptoms
being either a depressed mood or characterized by a loss of pleasure or interest[2] :
Depressed mood
Markedly diminished pleasure or interest in nearly all activities
Significant weight loss or gain or significant loss or increase in appetite
Hypersomnia or insomnia
Psychomotor retardation or agitation
Loss of energy or fatigue
Feelings of worthlessness or excessive guilt
Decreased concentration ability or marked indecisiveness
Preoccupation with death or suicide; patient has a plan or has attempted
suicide
See Clinical Presentation for more detail.
Diagnosis
Examination of patients with suspected bipolar affective disorder includes evaluation
using the Mental Status Examination as well as assessment of the following:
Appearance
Affect/mood
Thought content
Perception
Suicide/self-destruction
Homicide/violence/aggression
Judgment/insight
Cognition
Physical health
Testing
Although bipolar disorder is diagnosed based on the patients history and clinical
course, laboratory studies may be necessary to rule out other potential causes of the
patients signs and symptoms as well as to have baseline results before
administering certain medications.
Laboratory tests that may be helpful include the following:
CBC count
ESR levels
Fasting glucose levels
Electrolyte levels
Protein levels
Thyroid hormone levels
Creatinine and blood urea nitrogen levels
Liver and lipid panel
Substance and alcohol screening
22
Depending on the patients presentation, other laboratory tests may be indicated,

which may include the following:
Urinary copper levels

Antinuclear antibody testing
HIV testing
VDRL testing
Electrocardiography is important in elderly patients and before antidepressant

therapy. Electroencephalography and/or MRI may be appropriate for selected
patients.
See Workup for more detail.
Management
The treatment of bipolar affective disorder is directly related to the phase of the
episode (ie, depression or mania) and the severity of that phase, and it may involve
a combination of psychotherapy and medication. Always evaluate patients with
mania, hypomania, or mixed episode, and those with bipolar depression, for
suicidality, acute or chronic psychosis, or other unstable or dangerous conditions.[3]
Pharmacotherapy
Medications used to manage patients with bipolar disorder include the following:
Benzodiazepines (eg, lorazepam, clonazepam)
Antimanic agents (eg, lithium)
Anticonvulsants (eg, carbamazepine, valproate sodium, valproic acid,
divalproex sodium, lamotrigine, topiramate)
First-generation antipsychotics (eg, inhaled loxapine, haloperidol)
Second-generation antipsychotics (eg, asenapine, ziprasidone, quetiapine,
risperidone, aripiprazole, olanzapine, olanzapine and fluoxetine, clozapine,
paliperidone)
Phenothiazine antipsychotics (eg, chlorpromazine)
Dopamine agonists (eg, pramipexole)
Nonpharmacotherapy
Psychotherapy may help to decrease relapse rates, improve quality of life, and/or
increase functioning, or more favorable symptom improvement.[4]
Electroconvulsive therapy may be useful in selected patients with bipolar disorder.
See Treatment and Medication for more detail.
Background
Bipolar affective disorder, or manic-depressive illness (MDI), is a common, severe,
and persistent mental illness. This condition is a serious lifelong struggle and
challenge.[1] Other mental disorders and general medical conditions are more
prevalent in patients with bipolar disorders than in patients in the general population.
[5]
Among the general comorbid conditions, cardiometabolic conditions such as
cardiovascular disease, diabetes, and obesity are a common source of morbidity and
mortality for persons with bipolar disorder.
Bipolar disorder is characterized by periods of deep, prolonged, and profound
depression that alternate with periods of an excessively elevated or irritable mood
known as mania. This pattern of alternating severe depression and periods of mania
is characteristic of bipolar disorder type I (BPI), although in rarer cases, persons may
only experience episodes of mania. In practice, symptoms of mania and depression
can also occur together in what is termed a mixed state as the illness evolves. By
contrast, bipolar disorder type II (BPII) is diagnosed when episodes of severe
depression are punctuated with periods of hypomania, a less severe form of mania
that does not include psychosis or lead to gross impairment in functioning. A
diagnosis of cyclothymic disorder is given to individuals with periods of both
hypomanic and depressive symptoms without meeting the full criteria for mania,
hypomania or major depression.
The symptoms of mania include decreased sleep time accompanied by a decreased
need for sleep, pressured speech, increased libido, reckless behavior without regard
for consequences, grandiosity, and severe thought disturbances, which may or may
not include psychosis. Between these highs and lows, many patients, if adequately
medicated, usually experience periods of higher functionality and can lead a
productive life.
Unipolar (major depressive) disorder and bipolar disorder share depressive
symptoms, but bipolar disorder is defined by episodes of mania or hypomania. A
community lifetime prevalence of 4% for BPI and BPII disorder combined has been
suggested. The costs of bipolar disorder include the direct costs of treatment along
with the even more significant indirect costs of excess unemployment, decreased
productivity, and excess mortality; it is a severely impairing illness that affects many
aspects of patients' lives.[6]
In the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders,
(DSM-5), bipolar disorder constitutes a spectrum of mood disorders that includes
BPI, BPII, cyclothymiaand are thought to be a bridge between schizophrenia
spectrum disorders and depressive disorders in terms of the symptomology, family
history and genetics.[2]
Pathophysiology
The pathophysiology of bipolar affective disorder, or manic-depressive illness (MDI),
has not been determined, and no objective biologic markers correspond definitively
with the disease state. However, twin, family, and adoption studies all indicate that
bipolar disorder has a significant genetic component. In fact, first-degree relatives of
a person with bipolar disorder are approximately 7 times more likely to develop
bipolar disorder than the rest of the population, and the heritability of bipolar I
disorder (BPI) has recently been estimated at 0.73.[7]
23
Genetics
The genetic component of bipolar disorder appears to be complex: The condition is
likely to be caused by multiple different common disease alleles, each of which
contributes a relatively low degree of risk on its own. Such disease genes can be
difficult to find without very large sample sizes, on the order of thousands of
subjects.
When the genetics of bipolar disorder were first being studied, less precise tools
were available, but they still yielded interesting information. Many loci are now
known to be associated with the development of bipolar disorder. These loci are
grouped as major affective disorder (MAFD) loci and numbered in the order of their
discovery.
MAFD loci
MAFD1 is located at 18p and was originally described in a group of 22 patients with
bipolar disorder.[8] MAFD2 is located at Xq28 and, as such, is associated with an
X-linked inheritance pattern. The notion of an X-linked form of bipolar disorder is not
a new one, and at least one paper from the pregenetic era discusses this very
possibility.[9] MAFD3 is located at 21q22.13, and the association appears to be with
the TRPM2 gene.[10, 11] MAFD4 is located at 16p12 and has been associated with
susceptibility to bipolar disease in a cohort of 41 Finnish families.[12]
MAFD5 is located at 2q22-q24, and MAFD6 is located at 6q23-24. Interestingly,
evidence suggests a strong interaction between genes located in these 2 regions. It
has been concluded that the candidate gene in the MAFD5 locus shows epistatic
interaction with the MAFD6 risk locus.[13] MAFD7 is located at 22q12.1 and was
detected using microsatellite markers in a North American population; a large region
on 22q12 was associated with bipolar disorder in this study.[14] Further study in this
region showed a polymorphism in the promoter region of the XBP1 gene, which also
showed susceptibility to bipolar disorder in a Japanese cohort.[15] XBP1 appears to
be involved mainly in immune system function; thus,its influence on the susceptibility
of bipolar disorder is not understood.
MAFD8 is located at 10q21, and its discovery is the result of a large analysis of over
1.8 million variants in 4387 cases of bipolar disorder.[16] The association in this study
appears to be with the ANK3 gene, which is a gene of marked interest and is
therefore discussed at length below.[16] MAFD9 is located at 12p13.3, and its
discovery is the result of the same large analysis as MAFD8. The association in this
study appears to be with the CACNA1C gene.[16] Like ANK3, it remains a gene of
interest[17] and is also mentioned below.
Genome-wide association studies
The first series of genome-wide association studies (GWASs) for bipolar disorder
were published in 2007 and 2008,[18, 19, 20, 16] and a collaborative analysis of the last 3
studies gave combined support for 2 particular genes, ANK3 (ankyrin G) and
CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) in a
sample of 4387 cases and 6209 controls.[16] ANK3 is an adaptor protein found at
axon initial segments that regulates the assembly of voltage-gated sodium channels.
Both ANK3 and subunits of the calcium channel are downregulated in mouse brain
in response to lithium, which indicates a possible therapeutic mechanism of action of
one of the most effective treatments for bipolar disorder.[21]
Further evidence for association of bipolar disorder to CACNA1C was reported in
2011 in an ever-growing sample (numbering 11,974 bipolar disorder cases and
51,792 controls at the time of the report), providing overwhelming support for this
gene as a bipolar susceptibility locus.[17]
CACNA1C, on chromosome 12, encodes the alpha subunit of the L-type voltagegated calcium ion channel found in the brain. L-type calcium channel blockers have
been used to treat bipolar disorder, and there has been speculation that at least
some mood stabilizers may mediate their effects via modulating calcium channel
signaling in bipolar illness.
A joint analysis of the bipolar GWAS data was carried out, including GWAS data
from another large-scale study of schizophrenia published in the same issue. Again,
both ANK3 and CACNA1C came up positive in the combined data set, suggesting a
shared genetic basis for these disorders. A previous National Institutes of Health
(NIH) report on GWASs also underscored that bipolar disorder and schizophrenia
could indeed share common susceptibility genes on chromosome 6.[22]
In 2013, the Cross-Disorder Group of the Psychiatric Genomics Consortium
published results of their large GWAS study of psychiatric disorders, reporting that
specific single-nucleotide polymorphisms (SNPs) are associated with range of
childhood- or adult-onset psychiatric disorders.[23] The study comprised a combined
sample of 33,332 persons with schizophrenia, bipolar disorder, major depression,
attention deficit disorder and autism spectrum disorders and 27,888 controls of
European ancestry.[23]
Specific expression of common genetic variants at different times during
development, or in different regions of the brain, and in concert with other genetic
variants could help to explain differences in disease phenotypes. Genetic markers in
4 regions were associated with all 5 disorders, including variants in the CACNA1C
gene, another gene for an L-type voltage-gated calcium channel subunit, CACNB2,
and markers on chromosomes 3p21 and 10q24.[23] Although specific variants from
CACNA1C showed the strongest association when only samples from individuals
with bipolar disorder, major depression and schizophrenia were evaluated, the
majority of regions seemed to be associated with all 5 disorders, suggesting that
common risk alleles contribute to each phenotype, an effect described as pleiotropy.
As noted by the authors, although CACNB2 was not identified in previous GWASs of
a combined bipolar and schizophrenia sample, it was one of the main signals
detected in an independentGWASs of Han Chinese individuals with bipolar disorder.
[23]
Although the first GWAS of bipolar disorder used a much smaller sample size than
subsequent attempts, including an initial sample of 461 patients with bipolar disorder
from the National Institute of Mental Health (NIMH) consortium and a follow-up
sample of 563 patients collected in Germany, it still yielded interesting observations
24
that will need to be followed up in the larger samples mentioned earlier.[18] For
example, the strongest association signals were detected in genes also involved in
biochemical pathways regulated by lithium. The strongest hit was at a marker within
the first intron of diacylglycerol kinase eta (DGKH) gene. DGKH is a key protein in
the lithium-sensitive phosphatidyl inositol pathway.
Three of the other associated genes in this study also interact with the Wnt signaling
pathway upstream and downstream of glycogen synthase kinase 3-beta (GSK3).
Lithium-mediated inhibition of GSK3 is thought to result in downregulation of
molecules involved in cell death and upregulation of neuroprotective factors.
Additionally, GSK3 is a central regulator of the circadian clock, and lithiummediated modulation of circadian periodicity is thought to be a critical component of
lithiums therapeutic effect. In fact, another major coup for bipolar disorder research
has been the finding that a dominant-negative mutation in the CLOCK gene normally
contributing to circadian periodicity in humans results in maniclike behavior in mice,
[24]
including hyperactivity, decreased sleep, reduced anxiety, and an increased
response to cocaine. The latter finding also provides a shared biologic basis for the
high rate of substance abuse observed in clinical populations of subjects with bipolar
disorder.
Furthermore, the experimenters were able to abolish the manic behaviors by
rescuing expression of normal CLOCK specifically in the ventral tegmental area of
the mouse brain.[25] This area is rich in D2 receptors. Joseph Coyle hypothesized in
his commentary in the paper on the same issue that the efficacy of atypical
antipsychotics in acute mania might, in part, be achieved by their ability to lower
activity in neurons specifically within the ventral tegmental area.[26]
Although large-scale association studies of bipolar disorder are beginning to yield
results, one of the greatest obstacles to finding genes for such complex behavior is
the imprecision inherent in diagnosis of the disorder itself; objective criteria are
lacking. Therefore, some of the most exciting recent research is focused on defining
heritable, quantitative diagnostic measures that capture specific features of bipolar
disorder (termed endophenotypes) to refine the search for responsible genes.[27]
Such promising measures for bipolar disorder include structural brain phenotypes,
sleep and activity measures, neurocognitive measures, and gene expression
studies.[28] This collaborative research effort under the aegis of the National Institute
of Mental Health (NIMH) has been termed the Bipolar Phenome Project.[29]
Newer GWASs continue to find additional genes of interest which appear to be
associated with an increased risk of bipolar disorder. One study showed an
association between bipolar disorder and the NCAN gene.[30] This gene is expressed
in the brain and is involved in the migration of cells within the brain. In a mouse
model, it was observed that the NCAN product is most prevalent in the
hippocampus. There was no phenotypic defect in NCAN -deficient mice, but subtle
effects could not be excluded.[30]
Although most of the present research does not stratify by sex, a recent study looked
at association between estrogen receptor binding site variation with bipolar disorder
in females. In particular, the association is with the transglutaminase 2 (TGM2) gene,
which is known to be under estrogenic control.[31] This is further evidence of the
heterogeneity of bipolar disorder and also presents evidence to explain the
differences in the epidemiology of bipolar disorder between women and men.
Of additional interest, a number of studies suggest that certain large copy number
variants (greater than 100 kb) (includes both deletions and duplications) are
associated with psychiatric disease, with bipolar disease and schizophrenia being
the most commonly associated.[32] The implication is that possession of one of these
copy number variants may modify the phenotype to those who are at risk of
psychiatric disease.[32]
When investigators looked at microarray results for 1001 patients with bipolar
disorder and 1033 controls to quantify the risk of deletions throughout the genome
for patients with bipolar disorder, they found that 16.2% of patients with bipolar
disorder had deletions, whereas 12.3% of controls had deletions. In addition,
patients who had bipolar disorder and deletions more frequently had onset of mania
before age 18 years.[4]
Gene expression studies
Gene expression studies are one way of measuring the relative activity or inactivity
of genes, and they have already been proven useful for illuminating the
pathophysiology of psychiatric disorders, including bipolar disorder. For example,
studies comparing specific regions of postmortem brain tissue from persons with
bipolar disorder with tissue from control subjects have consistently shown that levels
of expression of oligodendrocyte-myelinrelated genes appear to be decreased in
brain tissue from persons with bipolar disorder.[33, 34, 35, 36] As with genetic studies,
gene expression profiling studies require very large sample sizes to produce
replicable data. Furthermore, they must focus on the correct brain region(s) thought
to be functioning differently in bipolar disorder, a point still under some debate.
Therefore, research in this area is ongoing and frequently subject to update.
Oligodendrocytes produce myelin membranes that wrap around and insulate axons
to permit the efficient conduction of nerve impulses in the brain. Therefore, loss of
myelin is thought to disrupt communication between neurons, leading to some of the
thought disturbances observed in bipolar disorder and related illnesses. Brain
imaging studies of persons with bipolar disorder also show abnormal myelination in
several brain regions associated with this illness.[37, 38] It can be useful to compare
data from gene expression studies with brain imaging studies of persons with bipolar
disorder to determine whether abnormalities of structure or function correlate with
changes in gene expression. In this case, structural neuroimaging studies also show
abnormal myelination in several brain regions associated with bipolar disorder.[37, 38]
Of note, many widely used psychotropic treatments including those for bipolar
disorder share signaling pathways that affect myelination, its plasticity,
andrepair;such pathways may promote myelination of neurons.[39]
Interestingly, gene expression and neuroimaging studies of persons with
schizophrenia and major depression also demonstrate similar findings, indicating
that mood disorders and schizophrenia may share some biologic underpinnings,
possibly related to psychosis. These types of data may also lead to the future
25
revision of psychiatric diagnostic manuals based on a new understanding of the

etiology of these disorders.
Another approach to delineating the pathophysiology of bipolar disorder involves
studying changes in gene expression induced in rodent brains after administration of
pharmacologic agents used to treat bipolar disorder. For example, investigators have
demonstrated that 2 chemically unrelated drugs (lithium and valproate) used to treat
bipolar disorder both upregulate the expression of the cytoprotective protein Bcl-2 in
the frontal cortex and the hippocampus of rat brains.[40] These types of studies are
also performed on human tissue by exposing cultured monocytes from peripheral
blood to lithium and other factors.
A postmortem study by Konradi et al of the hippocampus in both patients with bipolar
disorder and healthy persons found that the 2 groups did not differ in the total
number of hippocampal neurons.[41] However, patients with bipolar disorder had
reduced volume of nonpyramidal cell layers, a reduced number of somatostatinpositive and parvalbumin positive neurons, a reduced somal volume in cornu
ammonis sector 2/3, and reduced messenger RNA levels for somatostatin,
parvalbumin, and glutamic acid decarboxylase 1. These findings suggest alteration
of hippocampal interneurons in patients with bipolar disorder that might lead to
hippocampal dysfunction.
Neuroimaging studies of individuals with bipolar disorder or other mood disorders
also suggest evidence of cell loss or atrophy in these same brain regions. Thus,
another suggested cause of bipolar disorder is damage to cells in the critical brain
circuitry that regulates emotion. According to this hypothesis, mood stabilizers and
antidepressants are thought to alter mood by stimulating cell survival pathways and
increasing levels of neurotrophic factors to improve cellular resiliency. In 2008,
Mathew et al published a review of novel drugs and therapeutic targets for severe
mood disorders that focus on increasing neuroplasticity and cellular resiliency.[42]
Post et al had previously proposed a mechanism involving electrophysiologic
kindling and behavioral sensitization processes, which resonates with the neuronal
injury hypothesis.[24] They asserted that a person who is susceptible to bipolar
disorder experiences an increasing number of minor neurologic insultssuch as
those induced by drugs of abuse, stress-related excessive glucocorticoid stimulation,
oxidative or immune-mediated damagethat eventually resulting in mania that
further compromises the injured neurons.[24] Sufficient brain damage might persist to
cause mania to recur even with no or minor environmental or behavioral stressors.
Post et als formulation helps explain the effective role of anticonvulsant medications
(eg, carbamazepine and valproate) in the prevention of the highs and lows of bipolar
disorder. It also supports clinical observations that the more episodes a person
experiences, the more he or she will have in the future, underscoring the need for
long-term treatment.
For more information, see the Medscape Reference topic Genetics of Bipolar
Disorder.
Etiology
A number of factors contribute to bipolar affective disorder, or manic-depressive
illness (MDI), including genetic, biochemical, psychodynamic, and environmental
factors.
Genetic factors
Bipolar disorder, especially bipolar type I (BPI) disorder, has a major genetic
component, with the involvement of the ANK3,CACNA1C, and CLOCK genes.[18, 19,
20, 16, 17, 25, 43]
The evidence indicating a genetic role in bipolar disorder takes several
forms.
First-degree relatives of people with BPI are approximately 7 times more likely to
develop BPI than the general population. Remarkably, offspring of a parent with
bipolar disorder have a 50% chance of having another major psychiatric disorder.
One logitudinal study found that subthreshold manic or hypomanic episodes were a
diagnostic risk factor for the development of subsequent manic, mixed, or hypomanic
episodes in the offspring of parents with bipolar disorder. High-risk offspring,
compared with offspring of parents without bipolar disorder, also had higher rates of
ADHD, disruptive behavior disorders, anxiety disorders, and substance use
disorders.[44]
Twin studies demonstrate a concordance of 33-90% for BPI in identical twins. As
identical twins share 100% of their DNA, these studies also show that environmental
factors are involved, and there is no guarantee that a person will develop bipolar
disorder, even if they carry susceptibility genes.
Adoption studies prove that a common environment is not the only factor that makes
bipolar disorder occur in families. Children whose biologic parents have either BPI or
a major depressive disorder remain at increased risk of developing an affective
disorder, even if they are reared in a home with adopted parents who are not
affected. Frey and colleagues work supports the genetic contributions in bipolar
affective disorder.[45, 46]
Using probands from the Maudsley Twin Register in London, Cardno and colleagues
showed that schizophrenic, schizoaffective, and manic syndromes share genetic risk
factors and that the genetic liability was the same for schizoaffective disorder as for
the other 2 syndromes.[47] This finding suggests an independent genetic liability for
psychosis shared by both mood and schizophrenia spectrum disorders, as Berrettini
[48]
previously speculated and that has been confirmed in the recent large-scale
GWAS studies mentioned above.[17]
Gene expression studies also demonstrate that persons with bipolar disorder, major
depression, and schizophrenia share similar decreases in the expression of
oligodendrocyte-myelin-related genes and abnormalities of white matter in various
brain regions.
Biochemical factors
26
Multiple biochemical pathways likely contribute to bipolar disorder, which is why

detecting one particular abnormality is difficult. A number of neurotransmitters have
been linked to this disorder, largely based on patients responses to psychoactive
agents as in the following examples.
The blood pressure drug reserpine, which depletes catecholamines from nerve
terminals, was noted incidentally to cause depression. This led to the catecholamine
hypothesis, which holds that an increase in epinephrine and norepinephrine causes
mania and a decrease in epinephrine and norepinephrine causes depression.
Drugs used to treat depression and drugs of abuse (eg, cocaine) that increase levels
of monoamines, including serotonin, norepinephrine, or dopamine, can all potentially
trigger mania, implicating all of these neurotransmitters in its etiology. Other agents
that exacerbate mania include L-dopa, which implicates dopamine and serotoninreuptake inhibitors, which in turn implicate serotonin.
Evidence is mounting of the contribution of glutamate to both bipolar disorder and
major depression. A postmortem study of the frontal lobes of individuals with these
disorders revealed that the glutamate levels were increased.[49]
Calcium channel blockers have been used to treat mania, which may also result
from a disruption of intracellular calcium regulation in neurons as suggested by
experimental and genetic data. The proposed disruption of calcium regulation may
be caused by various neurologic insults, such as excessive glutaminergic
transmission or ischemia. Interestingly, valproate specifically upregulates expression
of a calcium chaperone protein, GRP 78, which may be one of its chief mechanisms
of cellular protection.
Hormonal imbalances and disruptions of the hypothalamic-pituitary-adrenal axis
involved in homeostasis and the stress response may also contribute to the clinical
picture of bipolar disorder.
Neurophysiologic factors
In addition to structural neuroimaging studies that look for volumetric changes in
brain regions regardless of brain activity, functional neuroimaging studies are
performed to find regions of the brain, or specific cortical networks, that are either
hypoactive or hyperactive in a particular illness. For example a meta-analysis by
Houenou et al found decreased activation and diminution of gray matter in a corticalcognitive brain network, which has been associated with the regulation of emotions
in patients with bipolar disorder.[50] An increased activation in ventral limbic brain
regions that mediate the experience of emotions and generation of emotional
responses was also discovered. This provides evidence for functional and anatomic
alterations in bipolar disorder in brain networks associated with the experience and
regulation of emotions.[50]
Psychodynamic factors
Many practitioners see the dynamics of manic-depressive illness as being linked
through a single common pathway. They see the depression as the manifestation of
losses (ie, the loss of self-esteem and the sense of worthlessness). Therefore, the
mania serves as a defense against the feelings of depression. Melanie Klein was
one of the major proponents of this formulation.
A study by Barnett et al found that personality disturbances in extraversion,
neuroticism, and openness are often noted in patients with bipolar disorder and may
be enduring characteristics.[51]
Environmental factors
In some instances, the cycle may be directly linked to external stresses or the
external pressures may serve to exacerbate some underlying genetic or biochemical
predisposition. For example, pregnancy is a particular stress for women with a
manic-depressive illness history and increases the possibility of postpartum
psychosis.[52]
Because of the nature of their work, certain individuals have periods of high
demands followed by periods of few requirements. For example, a landscaper and
gardener who was busy in the spring, summer, and fall became relatively inactive
during the winter, except for plowing snow. Consequently, he appeared manic for a
good part of the year, and then he would crash and hibernate during the cold
months.
Pharmacological factors
There is the risk that antidepressant treatment may propel the patient into a manic
episode. Researchers investigated the association between antidepressant therapy
and the later onset of mania/bipolar disorder. They analyzed the electronic records
of 21,012 adults presenting to South London and Maudsley National Health Service
(NHS) Trust (SLaM), a large provider of inpatient and community mental healthcare
in the United Kingdom, between April 1, 2006 and March 31, 2013 with unipolar
depression. The overall incidence rate of mania/bipolar disorder was 10.9 per 1000
person-years. The peak incidence of mania/bipolar disorder was seen in patients
aged between 26 and 35years (12.3 per 1000 person-years). Prior antidepressant
treatment was associated with an increased incidence of mania/bipolar disorder
ranging from 13.1 to 19.1 per 1000 person-years. Results suggest that in people with
unipolar depression, antidepressant treatment is associated with an increased risk of
subsequent mania/bipolar disorder. These findings highlight the importance of
considering risk factors for mania when treating people with depression.[53]
Epidemiology
United States statistics
The lifelong prevalence of bipolar affective disorder, or manic-depressive illness
(MDI), including subsyndromal forms in the United States has been noted to range
from 3.7% to 3.9%.[54] However, the prevalence in patients who present with
depression is higher in primary care (21-26%) and psychiatric clinic settings (28-
27
49%).[54] Studies also indicate differences in lifetime prevalence estimates for bipolar
disorder type I (BPI) (1.0%), bipolar disorder type II (BPII) (1.1%), and subthreshold
bipolar disorders (2.4-4.7%).[55]
International statistics
Globally, the lifelong prevalence rate of bipolar disorder is 0.3-1.5%. In crosssectional, face-to-face household surveys of more than 61,000 adults across 11
countries, Merikangas et al, using the World Mental Health version of the World
Health Organization Composite International Diagnostic Interview, version 3.0,
determined that the aggregate lifetime prevalences were 0.6% for BPI, 0.4% for
BPII, 1.4% for subthreshold bipolar disorder, and 2.4% for bipolar spectrum.[56] Yutzy
and colleagues reported an increase in the prevalence of BPI and BPII in recent
years.[57] This prevalence ranged from 0.4% to 1.6% between the mid 1970s and
2000; by the late 1990s to the 2000s, the prevalence had the climbed from
approximately 5% to 7%.[57]
Age-related differences in incidence

The age of onset of bipolar disorder varies greatly. For both BPI and BPII, the age
range is from childhood to 50 years, with a mean age of approximately 21 years.
Most cases of bipolar disorder commence when individuals are aged 15-19 years.
The second most frequent age range of onset is 20-24 years.
Some patients diagnosed with recurrent major depression may indeed have bipolar
disorder and go on to develop their first manic episode when older than 50 years.
These individuals may have a family history of bipolar disorder. However, for most
patients, the onset of mania in people older than 50 years should lead to an
investigation for medical or neurologic disorders, such as cerebrovascular disease.
For more information, see the Medscape Reference article Pediatric Bipolar Affective
Disorder.
Sex-related differences in incidence

BPI occurs equally in both sexes; however, rapid-cycling bipolar disorder (4
episodes/y) is more common in women than in men. The incidence of BPII is higher
in females than in males. Most studies report a nearly equal male-to-female ratio in
the prevalence of bipolar disorder; however, most studies also report an increased
risk in women for BPII/hypomania, rapid cycling, and mixed episodes.[58]
Prognosis
Bipolar affective disorder, or manic-depressive illness (MDI), has significant
morbidity and mortality rates. In the United States, during the early part of the 1990s,
the cost of lost productivity resulting from this disorder was estimated at
approximately $15.5 billion annually. Approximately 25-50% of individuals with
bipolar disorder attempt suicide, and 11% successfully commit suicide.
Additionally, a 2011 study from the United Kingdom suggested that for patients with
bipolar disorder, mortality 1 year after hospital discharge was also higher than that of
the general population for natural causes, chiefly respiratory and circulatory
disorders.[59]
Patients with BPI fare worse than patients with a major depression. Within the first 2
years after the initial episode, 40-50% of these patients experience another manic
attack. Only 50-60% of patients with BPI who are on lithium gain control of their
symptoms. In 7% of these patients, symptoms do not recur, 45% of patients
experience more episodes, and 40% go on to have a persistent disorder. Often, the
cycling between depression and mania accelerates with age.
Factors suggesting a worse prognosis include the following:
Poor job history

Substance abuse
Psychotic features
Depressive features between periods of mania and depression
Evidence of depression
Male sex
Pattern of depression-mania-euthymia
Factors suggesting a better prognosis include the following:
Length of manic phases (short duration)

Late age of onset
Few thoughts of suicide
Few psychotic symptoms
Few medical problems
Patient Education
Treatment of patients with bipolar affective disorder, or manic-depressive illness
(MDI), involves initial and ongoing patient education. To this end, a strong
therapeutic alliance is essential.
Educational efforts must be directed not only toward the patient but also toward their
family and support system. Furthermore, evidence continues to mount that these
educational efforts not only increase patient compliance and their knowledge of the
disease, but also their quality of life.[60]
An explanation of the biology of the disease must be provided. This decreases
feelings of guilt and promotes medication compliance. Information should be
provided on how to monitor the illness in terms of an appreciation of the early
warning signs, reemergence, and symptoms. Recognition of changes can serve as a
powerful preventive step.
Education must also encompass the dangers of stressors. Helping the individual
identify and work with stressors provides a critical aspect of patient and family
awareness. Efforts should be made to educate the patient about relapses within the
total context of the disorder.
28
Bipolar Affective Disorder Treatment & Management: Approach Considerations, Indi...
Bipolar Affective Disorder Treatment & Management

Approach Considerations
Always evaluate patients with mania, hypomania, or mixed episode, and those with
bipolar depression, for suicidality, acute or chronic psychosis, or other unstable or
dangerous conditions.[3]
The treatment of bipolar affective disorder, or manic-depressive illness (MDI), is
directly related to the phase of the episode (ie, depression or mania) and the severity
of that phase. For example, a person who is extremely depressed and exhibits
suicidal behavior requires inpatient treatment. In contrast, an individual with a
moderate depression who still can work would be treated as an outpatient.
Fortunately, most patients recover from the first manic episode, but their course
beyond that is variable.[75]
It is important to determine whether current medications may be causing the
patients manic, hypomanic, or mixed manic episode. In such patients, discontinue
antidepressants or other mania-inducing agents. However, antidepressants known to
have associated discontinuation syndromes should be tapered over several weeks.[3]
Evaluate and closely monitor patients with bipolar depression for the risk for mood
destabilization or switching to mania and for the presence of emergent symptoms
following initiation of pharmacotherapy for a depressive episode.[3] Initiate an
antipsychotic agent in patients with bipolar depression with psychotic features, and
consider psychosocial interventions (eg, psychoeducation; psychotherapy strategies
such as cognitive behavioral therapy [CBT], interpersonal and social rhythm therapy
[IPSRT], family focused therapy; chronic care model-based interventions).
The patients response to treatment may depend on the number of previous
episodes of bipolar disorder. In a report that analyzed pooled data, the importance of
early intervention was demonstrated with better treatment responses in individuals
who had earlier stages of illness.[76] Bipolar patients who experienced fewer previous
mania episodes (1-5) displayed a twofold increase in the treatment response rate to
olanzapine relative to those who had already experienced more than 5 previous
episodes.[76] In patients with depression, the response rates were also significantly
higher in patients with fewer episodes, although the findings were only for 2 of the
measured responses. In the maintenance studies, groups with fewer previous
episodes (1-5 or 6-10) experienced a 40-60% reduction in the risk of relapse to
either mania or depression compared to the group that had more than 10 previous
episodes.[76]
If the patient is in a short-term inpatient care unit and has not made significant
progress, reevaluate the management strategy. Transfer to a long-term inpatient
care unit might also be considered. If the patient is in a depressed or manic phase
and is not responding to medications, transfer the patient to a facility where
electroconvulsive therapy (ECT) can be administered. Additionally, consultation with
a psychiatric colleague or a psychopharmacologist is always appropriate if the
patient does not respond to conventional treatment and medication.
All patients with bipolar disorder need outpatient monitoring for both medications and
psychotherapy. In addition, these individuals need education regarding their
condition. The schedule must be regular, with great flexibility if they need extra
sessions.
The 2010 Veterans Administration/Department of Defense (VA/DoD) clinical practice
guideline for management of bipolar disorder recommends reassessing patients who
start treatment for acute bipolar mania, hypomania, or mixed episodes every 1-2
weeks for at least 6 weeks.[3] Patients with severe mania who are not hospitalized
should be reassessed every 2-5 days until symptoms improve. An absence of any
significant symptoms of mania or depression for 2 months should be considered to
be full remission and assessment of symptoms should then be continued periodically
to monitor for relapse.[3]
Evaluate the patients response to treatment with the same standardized tool at
follow-up visits, after changes in therapy, and with periodic assessments until
complete remission has been reached.[3] The Center for Quality Assessment and
Improvement in Mental Health (CQAIMH) provides assessment and screening tools
for bipolar disorder and suicide at: http://www.cqaimh.org/stable.html.
No surgical care is indicated for bipolar disorder. Historically, treatment was
attempted with psychosurgical procedures, such as prefrontal lobotomy. However,
lobotomy is no longer used in the clinical care of patients with bipolar disorder.
Indications for Inpatient Management

Patients diagnosed with bipolar mania or depression and severe symptoms must be
referred for urgent/emergent mental health intervention.[3] The indications for
inpatient treatment in a person with bipolar affective disorder, or manic-depressive
illness (MDI), include the following:
Danger to self
Danger to others
Delirium
Marked psychotic symptoms
Total inability to function
Total loss of control (eg, excessive spending, undertaking a dangerous trip)
Medical conditions that warrant medication monitoring (eg, substance
withdrawal/intoxication)
29
Patients with a possible diagnosis of bipolar depression must also be referred for
urgent/emergent mental health intervention if they present with serious delusion,
visual/auditory hallucinations, confusion, catatonic behavior, extreme
negativism/mutism, and/or inappropriate affect of a bizarre or odd quality.[3]
A patient with bipolar disorder, especially one in a depressive episode, may present
with a significant risk for suicide, especially those with an early onset of symptoms.
[77]
Serious suicide attempts and specific ideation with plans constitute clear
evidence of the need for constant observation and preventive protection; consider
referring these individuals to mental health specialty care.[3] Occasionally, depression
is so profound that the person cannot function at all; thus, the danger to the person
may come from other aspects of the disease. For example, a person in extreme
mania who foregoes sleep or food may be in a state of serious exhaustion. Leaving
such a person alone would be dangerous and not therapeutic.
Goldstein and associates followed the mental health of 413 youths diagnosed with
bipolar disorders and found that 76 (18%) attempted suicide at least once within 5
years of study; of these youths, 31 (8% of the overall group and 41% of those who
attempted suicide) made many attempts.[77] The investigators concluded that bipolar
disorder with early onset is associated with high suicide attempt rates. Therefore, the
patients severity of depression at presentation and their family history of depression
must be considered when evaluating youths with bipolar disorder and their suicide
risk.[77]
Patients with bipolar disorder can also become a threat to others. For example, a
patient experiencing a severe depression believed the world was so bleak that she
planned to kill her children to spare them from the worlds misery.
Sometimes, patients behaviors are totally out of control, which is a particular
concern during a manic episode. In this situation, patients behaviors are so beyond
limits that they destroy their career and can be harmful to those around them. For
example, a delusional patient having a manic episode believed everyone was
against him; he searched for a rifle in order to defend himself and to get them
before they got him.
Some patients with bipolar disorder have other medical conditions for which
medication monitoring is warranted. For example, patients with certain cardiac
conditions should be in a medical environment where the effects of the psychotropic
medications can be monitored and observed closely.
In the clearest case of the bipolar/depressed phase, the patient is suicidal and
homicidal in a few situations (this can result in homicide followed by suicide). In
these scenarios, institutioinal commitment is in order and indicated. In other
situations, the depression has led to an inability of the patient to work, eat, and
function; hospitalization is also indicated in these cases.
In the situation of a patient in the bipolar/manic phase, although the patient does not
show clear and dramatic evidence of homicide or suicide, a pattern of very poor
judgment and impairment emerges. Because of their behavior during the manic
phase, the person often does major damage to their finances, career, and position in
the community. This type of self-destructive mania calls for containment with good
documentation and family support.
Considerations for Partial Hospitalization or Day

Treatment
In general, patients with bipolar affective disorder, or manic-depressive illness (MDI),
who are candidates for partial hospitalization or day treatment experience severe
symptoms but have some level of control and a stable living environment. For
example, a patient with severe depression who has thoughts of suicide but no plans
to act upon them and who has a high degree of motivation can get well when given a
great deal of interpersonal support, especially during the day, and with the help of a
very involved and supportive family. The family needs to be home every night and
should be very concerned with the patients care.
Partial hospitalization also offers a bridge to return to work. Returning directly to
work is often difficult for patients with severe symptoms, and partial hospitalization
provides support and interpersonal relationships.
Considerations of Outpatient Treatment

Outpatient treatment for patients with bipolar affective disorder, or manic-depressive
illness (MDI), has 4 major goals, as follows:
1. Look at areas of stress and find ways to handle them: The stresses can stem
from family or work, but if they accumulate, they propel the person into mania
or depression; this is a form of psychotherapy
2. Monitor and support the medication: Medications make an incredible
difference, and the key is to obtain the benefits while avoiding adverse
effects; patients are ambivalent about their medicationsalthough they
recognize that the drugs help and prevent hospitalizations, they also resent
that they need them; the goal is to address their feelings and allow them to
continue with the medications
3. Develop and maintain the therapeutic alliance: This is one of the many
reasons for the practitioner to deal with the patients ambivalence about the
medications; over time, the strength of the alliance helps keep the patients
symptoms at a minimum and helps the patient remain in the community
4. Provide education (see Patient Education): The clinician must help educate
both the patient and the family about bipolar illness; patients and families
need to be aware of the dangers of substance abuse, the situations that
would lead to relapse, and the essential role of medications; support groups
for patients and families are of tremendous importance
Psychotherapy helps patients with bipolar disorder but does not cure the disorder by
itself. When Schottle and colleagues looked at psychotherapy for patients, family,
and caregivers, they found that although results were heterogeneous, most studies
demonstrated relevant positive results in regard to decreased relapse rates,
improved quality of life, increased functioning, or more favorable symptom
improvement.[4]
30
Somatic health issues in individuals with bipolar disorder are ubiquitous,

underrecognized, and suboptimally treated.[78] Therefore, practitioners must pay
attention to patients medical conditions, including cardiovascular concerns,
diabetes, endocrine problems, infections, urinary complications, and electrolyte
imbalances. In view of the possible medical complications, medical follow-up is
important. Persons with bipolar disorder often have difficulty obtaining primary
physician care.[79]
Patients with chronic medical illnesses and depression should be treated with a
comprehensive approach involving the patient, the family, the support team, the
physician, other professionals, and community resources. Such models, called
Collaborative Chronic Care Models (CCMs), have been developed to improve
outcomes in chronically ill patients treated in the primary care setting who also suffer
from depression. CCMs were defined a priori as interventions with at least 3 of the 6
components of the Improving Chronic Illness Care initiative, as follows:
Patient self-management support

Clinical information systems
Delivery system redesign
Decision support
Organizational support
Community resource linkages
When Woltmann et al examined this approach in patients with bipolar disorder, they
concluded that CCMs can improve both mental and physical outcomes for patients
with mental disorders across a wide range of care settings.[80] CCMs also provide a
robust clinical and policy framework for the integration of care. The review included
78 articles, yielding 161 analyses from 57 trials.[80]
Pharmacologic Therapy
Appropriate medication depends on the stage of the bipolar affective disorder, or
manic-depressive illness (MDI), the patient is experiencing. Thus, a number of drugs
are indicated for an acute manic episode, primarily the antipsychotic agents,
valproate, and benzodiazepines (eg, lorazepam, clonazepam). The choice of agent
depends on the presence of symptoms such as psychotic symptoms, agitation,
aggression, and sleep disturbance. (See the list of medications for bipolar disorder in
Table 1, below.) For patients with bipolar affective disorder in the depressed phase,
the Medscape Reference article Depression provides antidepressant guidelines.
Table 1. FDA-Approved Bipolar Treatment Regimens (Open Table in a new window)
Generic Name
Trade
Name
Manic Mixed Maintenance Depression
Valproate
Depakote
Carbamazepine
extended release
Equetro
Lamotrigine
Lamictal
Lithium
X
X
X
X
Aripiprazole
Abilify
Ziprasidone
Geodon
Risperidone
Risperdal
Asenapine
Saphris
Quetiapine
Seroquel
Chlorpromazine
Thorazine X
Cariprazine
Vraylar
Olanzapine
Zyprexa
Olanzapine/fluoxetine
combination
Symbyax
X
X
FDA = United States Food and Drug Administration.
Source: Gutman DA, Nemeroff C.Medscape Education. Atypical antipsychotics in

bipolar disorder.Available at: http://www.medscape.org/viewarticle/554128.
Accessed: June 27, 2007.[81]
Bauer and colleagues have suggested 2 approaches to treatment options in bipolar

patients.[82] First, in a patient with bipolar depression who is not currently being
treated with a mood-stabilizing agent (de novo depression, first or subsequent
episode), options include quetiapine or olanzapine, with carbamazepine and
lamotrigine as alternatives.[82] Antidepressants are options for short-term use, but it
remains controversial as to whether it is better to administer them in combination
with mood-stabilizing agents or as monotherapy. Second, if the patient is already
optimally treated with a mood-stabilizing agent (appropriate dose, good compliance)
such as lithium, an option would be lamotrigine. No evidence suggests additional
benefit from antidepressants if a patient is already being treated with a mood
stabilizer, but this often tried in practice.[82]
One cautionary note of interest: Post and colleagues found that the more different
antidepressant trials the patient with bipolar disorder has received, the less
responsive they become to treatment.[83]
Inhaled loxapine (Adasuve) is the first noninjectable therapy approved by the FDA to
treat acute agitation associated with schizophrenia and bipolar disorder type I (BPI).
The FDA approval was based on 2 phase III studies of 658 individuals; statistically
significant reductions in agitation were apparent starting 10 minutes following
administration compared with placebo, and these effects were sustained at 2 hours.
[84, 85]
31
Severe mania or mixed episodes

Combined therapy with an antipsychotic agent and another antimanic medication is
recommended for patients with severe mania or mixed episodes, with or without
psychotic features.[3] Thus, lithium, a drug commonly used for prophylaxis and
treatment of manic episodes, or valproate may be used in combination with
antipsychotic agents (eg, severe mania: olanzapine, quetiapine, aripiprazole,
risperidone, or possibly ziprasidone; severe mixed episode: aripiprazole, olanzapine,
risperidone, haloperidol or possibly quetiapine or ziprasidone).[3]
Despite the serious side effects associated with clozapine, the Veterans
Administration/Department of Defense (VA/DoD) suggest this drug may be added to
existing medications if it was successfully used previously for severe mania or mixed
episodes or if other antipsychotic agents are unsuccessful.[3]
Reevaluate nonhospitalized patients being treated for severe mania or mixed
episodes every 2-5 days until symptomatic improvement, and adjust medication
dosages and regimens as needed.[3] The therapeutic range of lithium is a serum
trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for
carbamazepine, 4-12 mcg/mL. If the patients serum concentrations of their
medication fall below the therapeutic range, adjust the drugs dose to the maximum
range. For medications without known therapeutic plasma concentrations, increase
the dose until symptomatic improvement, patient intolerance, or the manufacturers
maximum dose limits have been reached.[3]
Mania/hypomania or mixed episodes

Initiate lithium, valproate, carbamazepine, aripiprazole, olanzapine, quetiapine,
risperidone, or ziprasidone in patients with mania.[3] In patients with mixed episodes,
initiate therapy with valproate, carbamazepine, aripiprazole, olanzapine, risperidone,
or ziprasidone. Consider clozapine, haloperidol, or oxcarbazepine in patients with
mania or mixed episodes, and consider lithium or quetiapine in those with mixed
episodes.[3]
Researchers have demonstrated a link between a locus on chromosome 21 and
patient response to lithium. The study found that a single locus of four linked SNPs
on chromosome 21 met genome-wide significance criteria for association with lithium
response. Carriers of the SNPs had significantly lower rates of disease relapse than
carriers of the alternate alleles.[86]
It is not recommended that topiramate, lamotrigine, and gabapentin be used to treat
patients with mania or mixed episodes.[3]
Bipolar depression
The American Psychiatric Association's (APA) 2005 guideline watch for the
treatment of patients with bipolar disorder noted that medications having the
strongest evidence for efficacy for the acute treatment of depression in BPI are the
olanzapine-fluoxetine combination, quetiapine, and lamotrigine.[54] Furthermore,
there is some evidence that pramipexole may be helpful as an adjunctive agent,
although only modest evidence exists for the efficacy of an antidepressant with
adjunctive mood stabilizer. Antidepressants in the absence of a mood stabilizer are
not recommended by the APA for BPI patients.[54]
Monotherapy
The VA/DoD considers first-line monotherapy in adult patients with bipolar
depression to include quetiapine, lamotrigine, or lithium.[3] Cautiously consider
olanzapine monotherapy due to its adverse effects. Second-line pharmacotherapy
includes the combination of olanzapine/fluoxetine owing to its side-effect profile of
weight gain, diabetes risk, and hypertriglyceridemia.[3]
Although the VA/DoD found insufficient evidence for or against the use of valproate,
carbamazepine, topiramate, risperidone, ziprasidone, or clozapine for managing
bipolar depression, it did advise against aripiprazole monotherapy in patients with
acute bipolar depression, except in cases in which there was[3] : (1) a previous good
response during depression without a switch to mania or (2) a history of treatment of
refractory depression.
Combination therapy
In patients whose bipolar depression is unresponsive to monotherapy, consider the
combination of lithium with lamotrigine.[3] Alternatively, consider short-term
augmentation of antidepressant agents with a selective serotonin reuptake inhibitor
(SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), bupropion, and
monoamine oxidase inhibitor (MAOI); patients using this treatment strategy must be
closely monitored for triggering of manic symptoms.[3]
As in severe mania or severe mixed episodes, consider adding clozapine for
augmentation, and closely monitor the patient for metabolic or other adverse effects.
[3]
Because of the known complications involved with clozapine, it is recommended
that a psychiatric consultation be initiated.
The VA/DoD found insufficient evidence for or against the use of augmentation with
aripiprazole, olanzapine, risperidone, haloperidol, oxcarbazepine, topiramate,
ziprasidone, valproate, or carbamazepine in bipolar depression.[3] However, the
VA/DoD advised against the use of gabapentin and tricyclic antidepressant agents
(TCAs) for monotherapy or augmentation in patients with acute bipolar depression,
except in cases in which there was[3] : (1) a previous good response during
depression without a switch to mania or (2) a history of treatment of refractory
depression.
Dosing or medication adjustments
Switch to another effective treatment for patient intolerance to side effects. For
patients that switch into mania or hypomania or enter a mixed manic state, follow the
recommendations discussed above in Mania/hypomania or mixed episodes.
Reevaluate patients every 1-2 weeks for a minimum of 6 weeks. As noted earlier,
the therapeutic range of lithium is a serum trough concentration between 0.6-1.2
32
mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL.[3] If the
patients serum concentrations of their medication fall below the therapeutic range,
adjust the drugs dose to the maximum range. For medications without known
therapeutic plasma concentrations, increase the dose until symptomatic
improvement, patient intolerance, or the manufacturers maximum dose limits have
been reached.[3]
In patients with a partial treatment response (no response 2-4 weeks after initiation
of an adequate medication dose), consider augmenting the medication with
additional agents as discussed under Combination therapy,discontinuing the current
drug (tapered withdrawal with monitoring for antidepressant syndrome and mood
destabilization) and switching to another effective agent, or electroconvulsive
therapy (ECT) if multiple trials of switching medications/augmentation strategies
have been unsuccessful.[3]
Other considerations
A study by Bauer et al suggested that lithium may also have a neuroprotective role.
However, this agent is also associated with increased risk of reduced urinary
concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The
consistent finding of a high prevalence of hyperparathyroidism should prompt
physicians to check patient calcium concentrations before and during treatment.
Lithium is not associated with a significant reduction in renal function in most
patients, and the risk of end-stage renal failure is low.[88]
[87]
Atypical antipsychotics are increasingly being used for the treatment of both acute
mania and mood stabilization. The broad range of antidepressants and ECT are
used for an acute depressive episode (ie, major depression). However, ECT may
also be considered for patients with severe mania or treatment-resistant mania,
those who prefer ECT, and pregnant women with severe mania.[3] Ansari and Osser
developed a very useful algorithm for the Harvard South Shore Program to treat a
bipolar patient in a depressed phase through an organized, sequential, and
evidence-supported approach.[89] Finally, another set of medications is chosen for
the maintenance and preventive phases of treatment.
Diazgranados and colleagues reported that for patients with treatment-resistant
bipolar depression, impressive and swift antidepressant effects occurred when a
single intravenous (IV) dose of the N -methyl-D -aspartate (NMDA) antagonist
ketamine was administered.[90] Increasingly, the role of glutamate in mood disorders
is being researched, and experimental evidence shows that the NMDA receptor
antagonist ketamine may be helpful in short-term treatment of depression, even in
the context of bipolar disorder. However, it is important to note that the benefit of
such treatment disappeared after 4 days.
Although antidepressant medications are most often prescribed for patients with
bipolar disorder who are experiencing an acute depression, a study found that
antidepressants were not statistically superior to placebo or other current standard
treatment for bipolar depression.[91]
Clinical experiences have shown that patients with bipolar disorder have fewer
episodes of mania and depression when treated with mood-stabilizing drugs.[92]
These medications not only serve to stabilize the patients mood, as the name
implies, they can also dampen extremes of mania or depression. Kessing et al found
that, in general, lithium was superior to valproate.[93]
Atypical antipsychotics (including ziprasidone, quetiapine, risperidone, aripiprazole,
olanzapine, and asenapine) are also now frequently used to stabilize acute
maniaor even to treat bipolar depression in some cases.
In the treatment of depression associated with bipolar disorder type II, Swartz and
associates reported that 95% of relevant trials were published later than 2005.[94]
They noted compelling evidence for the efficacy of quetiapine and preliminary
support for the efficacy of lithium, antidepressants, and pramipexole. However,
mixed support was noted for lamotrigine.[94]
Maintenance
The role of mood stabilizers and antipsychotic medications in maintaining patients
with bipolar disorder is well documented,[95] as is the use of long-acting
antipsychotics to help with the maintenance phase. The APAs 2005 guideline watch
for the treatment of patients with bipolar disorder considered both lamotrigine and
lithium to have substantial utility in the maintenance treatment of patients with bipolar
disorder.[54]
Popovic et al suggested the use of a Polarity Index to guide the choice of
maintenance therapy in bipolar patients.[96] Based on results from randomized,
placebo-controlled trials, the investigators indicated that this index may provide a
measure of the relative preventive antimanic versus antidepressive efficacy of drugs
that are used to treat bipolar disorder.[96] They defined a Polarity Index value greater
than 1.0 as having a relative greater antimanic prophylactic efficacy, whereas a
value less than 1.0 would have a relative greater antidepressive efficacy. The
following are this studys polarity indices results for maintenance drugs in bipolar
disorder[96] :
Risperidone: 12.09
Aripiprazole: 4.38
Ziprasidone: 3.91
Olanzapine: 2.98
Lithium: 1.39
Quetiapine: 1.14
Lamotrigine: 0.40
Note that Popovic et al indicated the respective polarity indices for valproate and
oxcarbazepine were potentially unreliable owing to the failure of their maintenance
trials.[96]
There have been concerns that ziprasidone may have adverse effects on body
weight, fasting lipids, and fasting glucose. When Pappadopulos et al looked at a
comprehensive set of analyses of metabolic alternations in patients on this
medication, they found no significant differences between the ziprasidone and
33
placebo groups in levels of fasting triglycerides, total cholesterol, low-density

lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the
controlled studies.[97]
According to a multiple treatments meta-analysis of treatments for acute mania, the
most efficacious treatments are haloperidol, risperidone, and olanzapine,
significantly outperforming primary mood stabilizers and other antipsychotic
medications.[98] In several randomized, double-blind, controlled studies, olanzapine
monotherapy was significantly more effective in treating manic or mixed episodes
than haloperidol[99] or divalproex monotherapy.[100] The adjunctive use of olanzapine
with divalproex or lithium,[101] or of risperidone with divalproex or lithium, was also
significantly more effective than divalproex or lithium alone.[102, 103]
As outlined in the APAs 2002 clinical practice guideline,[104] benzodiazepines have
sedative effects, which may make them useful adjunctive medications until antimanic
medications take effect. Additionally, the guideline stated that manic symptoms may
be treated with chlorpromazine, which was deemed superior to placebo in a
randomized trial and was deemed comparable to lithium (for controlling manic and
psychotic symptoms) in acute treatment comparison trials.
Children and adolescents who have bipolar disorder are particularly challenging to
treat, and their discussion is beyond the scope of this article (see the Medscape
Reference article Pediatric Bipolar Affective Disorder). However, Hamrin and
Iennaco developed guidelines and recommendations for medications and
management approaches after an extensive literature review using research findings
on medication effectiveness in this population.[105]
There is evidence that risperidone may be the best first-line treatment for childhood
mania, as shown in a randomized controlled trial with patients aged 6 to 15 years
with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision, (DSM-IV-TR) diagnosis of BPI (manic or mixed phase).[106] Specifically,
risperidone was significantly more effective than lithium or divalproex sodium for the
initial treatment of childhood mania; however, use of risperidone had the potential for
serious metabolic side effects.[106]
Caution in polyantipsychotic therapy in bipolar disorder

In August 2010, the FDA announced that lamotrigine carries a risk of aseptic
meningitis.[107]
In a study that sought to evaluate the safety and tolerability of second-generation
antipsychotic (SGA) polytherapy compared with monotherapy in patients with bipolar
disorder receiving open naturalistic treatment in the 22-site Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD), Brooks et al concluded that
although polytherapy was fairly common in bipolar disorder, it was also associated
with increased side effects (eg, dry mouth, sexual dysfunction, and constipation) and
increased health service use (almost threefold) but not with improved clinical status
or function.[108] Therefore, polytherapy in bipolar disorder may incur important
disadvantages without clear benefit, warranting careful consideration before
undertaking such interventions.[108]
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is useful in a number of instances in patients with
bipolar affective disorder, or manic-depressive illness (MDI), such as the following[3] :
When rapid, definitive medical/psychiatric treatment is needed
When the risks of ECT are less than that of other treatments
When the bipolar disorder is refractory to an adequate trial with other
treatment strategies
When the patient prefers this treatment modality
Often, the severity of the patients symptoms, the lack of response to medications, or
the presence of contraindications to certain medications necessitates the use of
ECT. This treatment modality has proven to be highly effective in the treatment of
acute mania.
The 2010 Department of Veterans Affairs/Department of Defense (VA/DoD) clinical
practice guideline for management of bipolar disorder indicates ECT is the primary
therapy in bipolar disorder patients that present with psychotic symptoms, catatonia,
severe suicidality, food refusal leading to nutritional compromise, or who have a
history of previous positive response to ECT.[3] Indeed, in a review of 50 years
experience with ECT for acute manic episodes, data from early literature revealed
that 313 of 400 patients with acute mania who received ECT showed significant
clinical improvement.[109]
Dietary and Activity Measures

Unless the patient with bipolar affective disorder, or manic-depressive illness (MDI),
is on monoamine oxidase inhibitors (MAOIs), no special diet is required. Patients
should be advised not to make significant changes in their salt intake, because
increased salt intake may lead to reduced serum lithium levels and reduced efficacy,
and reduced intake may lead to increased levels and toxicity.
Although a meta-analysis by Starris et al found strong evidence that bipolar
depressive symptoms may be improved by adjunctive use of omega-3, omega-3
does not improve bipolar mania.[110]
Patients in the depressed phase are encouraged to exercise. These individuals
should try to develop a regular daily schedule of major activities, especially times of
going to bed and waking up. Propose a regular exercise schedule for all patients,
especially those with bipolar disorder. Both the exercise and the regular schedule
are keys to surviving this illness. However, increases in exercise level, with
increased perspiration, can lead to increased serum lithium levels and lithium
toxicity.
Complications
34
Bipolar Affective Disorder Medication: Anxiolytics, Benzodiazepines, Mood stabilize...
Bipolar Affective Disorder Medication

Medication Summary
Appropriate medication for managing bipolar affective disorder, or manic-depressive
illness (MDI), depends on the stage the patient is experiencing. The choice of agent
depends on the presence of symptoms such as psychotic symptoms, agitation,
aggression, and sleep disturbance. Drug categories include mood stabilizers,
anticonvulsants, and antipsychotics
Anxiolytics, Benzodiazepines
Class Summary
By binding to specific receptor sites, benzodiazepines appear to potentiate the
effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA
neurotransmission and the action of other inhibitory transmitters.
Lorazepam (Ativan)
Lorazepam is an anxiolytic hypnotic with an intermediate onset of effects and a
relatively intermediate half-life. By increasing the action of GABA, which is a major
inhibitory neurotransmitter in the brain, it may depress all levels of the central
nervous system (CNS), including the limbic and reticular formation.
Clonazepam (Klonopin)
Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA
inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses
muscle contractions by facilitating inhibitory GABA neurotransmission and other
inhibitory transmitters.
Mood stabilizers
Class Summary
Lithium is the drug commonly used for prophylaxis and treatment of manic episodes.
A 2012 study suggested that lithium may also have a neuroprotective role.[83]
However, this agent is also associated with an increased risk of reduced urinary
concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The
consistent finding of a high prevalence of hyperparathyroidism should prompt
physicians to check patient calcium concentrations before and during treatment.
Lithium is not associated with a significant reduction in renal function in most
patients, and the risk of end-stage renal failure is low.[87] Lithium therapy may serve
to protect and preserve the hippocampal volumes, in contrast to patients with major
depression (ie, unipolar), who show diminished hippocampal volumes.[88]
Furthermore, recognizing that patients with bipolar affective disorder are at risk for
suicide, lithium may also have some anti-suicidal action. A report from Lewitka and
Bauer suggest that lithium may be an option for patients with affective disorders who
are at risk for suicide. However, they caution that lithium is still a medication that
requires careful assessment and monitoring. Patient adherence is essential.[43]
Many female patients with bipolar disorder will discontinue their lithium medication
when they become pregnant.[118]
Lithium carbonate (Lithobid)

Lithium is considered a first-line agent for long-term prophylaxis in bipolar illness,
especially for classic bipolar disorder with euphoric mania. It also can be used to
treat acute mania, although it cannot be titrated up to an effective level as quickly as
valproate can. Evidence suggests that lithium, unlike any other mood stabilizer, may
have a specific antisuicide effect.
Monitoring blood levels is critical with this medication. Serum levels should be
determined twice weekly during the acute phase, and until the serum level and
clinical condition of the patient has been stabilized.
Anticonvulsants
Class Summary
Anticonvulsants have been effective in preventing mood swings associated with
bipolar disorder, especially in those patients known as rapid cyclers. For the
depressed phase, mood stabilizers, such as lithium and lamotrigine, are preferred,
because antidepressants may propel a patient into a manic episode or exacerbate
irritability in mixed-symptom mania. Gabapentin, although not a mood stabilizer, also
may have anxiolytic properties.The most widely used anticonvulsants have been
35
carbamazepine, valproate, and lamotrigine. More recently, topiramate and

oxcarbazepine also are being tried.
Note that the Department of Veterans Affairs/Department of Defense (VA/DoD) do
not recommend lamotrigine, topiramate, and gabapentin in patients with mania or
mixed episodes.[3]
Carbamazepine (Equetro)
Carbamazepine is effective in patients who have not had a clinical response to
lithium therapy and who have rapid-cycling bipolar disorder. Its efficacy is not well
established for long-term use; therefore, periodically reevaluate the long-term risks
and benefits of carbamazepine for individual patients. This drug can also act to
inhibit seizures induced through the kindling effect, which is thought to occur by way
of repeated limbic stimulation.
Valproate sodium, valproic acid, divalproex sodium (Depakene,

Depakote, Depakote ER, Depacon, Stavzor)
Valproate has proven effectiveness in treating and preventing mania. It is classified
as a mood stabilizer and can be used alone or in combination with lithium. This
agent is useful in treating patients with rapid-cycling bipolar disorders and has been
used to treat aggressive or behavioral disorders. A combination of valproic acid and
valproate has been effective in treating persons in manic phase, with a success rate
of 49%.
Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine is an anticonvulsant that appears to be effective in the treatment of the
depressed phase in bipolar disorders. It is used for the maintenance treatment of
bipolar I disorder to delay the time to occurrence of mood episodes (depression,
mania, hypomania, mixed episodes) in adults treated for acute mood episodes with
standard therapy.
Topiramate (Topamax)
Topiramate has an off-label indication for the treatment of bipolar disease. In a small
retrospective review, marked improvement occurred in 62% of patients when
topiramate was added to their current regimen.[115] It is unclear if topiramate's
efficacy occurs only as adjunctive treatment. More studies are needed to examine
potential benefits of this drug in treating bipolar. Unlike conventional neuroleptics,
topiramate is not associated with weight gain.
Antipsychotics, 2nd Generation

Class Summary
Second-generation, or atypical, antipsychotics are increasingly being used for
treatment of both acute mania and mood stabilization in patients with bipolar I
disease.
Asenapine (Saphris)
Asenapine is indicated as monotherapy for the acute treatment of manic or mixed
episodes that are associated with bipolar I disorder. It is also indicated as adjunctive
therapy with lithium or valproate for the acute treatment of manic or mixed episodes
associated with bipolar I disease. The efficacy of asenapine is thought to be
mediated through a combination of antagonist activity at dopamine 2 and serotonin
(5-HT2) receptors.
Ziprasidone (Geodon)
Ziprasidone is approved for the treatment of acute or mixed episodes that are
associated with bipolar disorder. It can be used as maintenance treatment or as an
adjunct to lithium or valproate.
Quetiapine (Seroquel, Seroquel XR)

Quetiapine is indicated for acute treatment of manic (immediate release and
extended release [XR]) or mixed (XR) episodes that are associated with bipolar I
disorder. It can be used as monotherapy or adjunctively with agents such as lithium
or divalproex.
Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Risperidone is indicated for short-term treatment of acute manic or mixed episodes
that are associated with bipolar I disorder. It can be used alone or in combination
with lithium or valproate. Risperidone can be used in adults and adolescents aged
10-17 years with bipolar I disorder.
36
Aripiprazole (Abilify, Abilify Discmelt)

Aripiprazole is indicated for the acute and maintenance treatment of manic or mixed
episodes associated with bipolar I disorder. It can be used alone or in combination
with lithium or valproate.
Olanzapine (Zyprexa, Zyprexa Zydis)

Olanzapine is used for the acute and maintenance treatment of manic or mixed
episodes associated with bipolar I disorder. It can be used alone or in combination
with lithium or valproate. Olanzapine can be used in adults and adolescents aged
13-17 years with bipolar I disorder.
Olanzapine and fluoxetine (Symbyax)

The drug combination includes olanzapine, a second-generation antipsychotic, and
fluoxetine, a selective serotonin reuptake inhibitor. This drug is indicated for the
acute treatment of depressive episodes associated with bipolar I disorder in adults.
The clinical effects of this agent have not been studied in patients younger than 18
years.
Clozapine (Clozaril, FazaClo ODT)

Clozapine has an off-label indication for treatment of acute manic episodes
associated with bipolar disorder and treatment of refractory bipolar mania. This
agent demonstrates weak D2 receptor and D1 receptor blocking activity. Clozapine
also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic
receptors.
Paliperidone (Invega)
Paliperidone may be used for refractory, moderate to severe mania alone or in
combination with lithium or valproate. This agent is typically reserved for patients
who decline electroconvulsive therapy (ECT) and who do not respond to medication
combinations involving lithium or valproate plus aripiprazole, haloperidol, or another
first-generation antipsychotic.
Cariprazine (Vraylar)
Precise mechanism by which cariprazine works for bipolar disorder is unknown.
Efficacy could be mediated through a combination of partial agonist activity at central
dopamine (D2) and serotonin 5-HT1A receptors. It is indicated for manic or mixed
episodes associated with bipolar 1 disorder.
Antipsychotics, 1st Generation

Class Summary
First-generation antipsychotics, also known as conventional or typical antipsychotics,
are efficacious for treating both psychotic and nonpsychotic manic and mixed
episodes, as well as hypomania. These agents are strong dopamine D2 antagonists.
However, each drug in this class has various effects on other receptors, such as
5-HT2 serotonin, alpha1, histaminic, and muscarinic receptors.
Loxapine inhaled (Adasuve)

The mechanism of action for loxapine is unknown, but it is theorized to antagonize
central dopamine D2 and serotonin 5-HT2a receptors. The inhaled dosage form is
indicated for acute treatment of agitation associated with schizophrenia or bipolar I
disorder in adults.
Haloperidol (Haldol)
Haloperidol is used for the acute treatment of mania or mixed episodes in patients
with bipolar disorder. It can be used alone or in combination with lithium or valproate
in an adult patient. Haloperidol blocks postsynaptic dopamine receptors (D2) in the
mesolimbic system and increases dopamine turnover by blockade of the D2
somatodendritic autoreceptor
Antipsychotics, Phenothiazine
Class Summary
Phenothiazine antipsychotics, which are classified as first-generation antipsychotics,
are efficacious for treating both psychotic and nonpsychotic manic and mixed
episodes, as well as hypomania.
Chlorpromazine (Thorazine)
Chlorpromazine is used to treat manic and mixed episodes in patients with bipolar I
disorder. It can be used alone or in combination with lithium or valproate.
Chlorpromazine blocks postsynaptic dopamine receptors (D2) in the mesolimbic
37
system and increases dopamine turnover by blockade of the D2 somatodendritic

autoreceptor
Antiparkinson Agents, Dopamine Agonists

Class Summary
Dopamine agonists are non-ergot agents that bind to D2 and D3 dopamine receptors
in the striatum and substantia nigra.
Pramipexole (Mirapex, Mirapex ER)

Pramipexole is used as add-on therapy for patients whose condition is refractory to
combination therapy and have bipolar depression. Pramipexole is a non-ergot, full
dopamine agonist that binds to D2 and D3 dopamine receptors.
38
Contributor Information and Disclosures

Author
Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty, Boston University, Boston, MA
and Daniel Webster College, Nashua, NH
Stephen Soreff, MD is a member of the following medical societies: ACMHA: The College for Behavioral Health
Leadership
Coauthor(s)
Lynne Alison McInnes, MD, MS Associate Clinical Professor of Psychiatry, University of California, San
Francisco, School of Medicine
Lynne Alison McInnes, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American
Psychiatric Association, American Society of Human Genetics
Chief Editor
Iqbal Ahmed, MBBS, FRCPsych(UK) Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical
Professor of Psychiatry, Uniformed Services University of the Health Sciences; Clinical Professor of Psychiatry,
Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine
Iqbal Ahmed, MBBS, FRCPsych(UK) is a member of the following medical societies: Academy of Psychosomatic
Medicine, American Neuropsychiatric Association, American Society of Clinical Psychopharmacology, Royal
College of Psychiatrists, American Association for Geriatric Psychiatry, American Psychiatric Association
Acknowledgements
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College
of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
References
1. Bowden C, Singh V. Long-term management of bipolar disorder. Available at
http://www.medscape.com/viewprogram/2686.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
Washington, DC: American Psychiatric Association; 2013.
3. 69. Management of Bipolar Disorder Working Group. VA/DoD clinical practice guideline for management of
bipolar disorder in adults. Washington, DC: Department of Veterans Affairs, Department of Defense; 2010.
Available at http://guideline.gov/content.aspx?id=16314. Accessed: May 15, 2012.
4. Zhang D, Cheng L, Qian Y, Alliey-Rodriguez N, Kelsoe JR, Greenwood T, et al. Singleton deletions
throughout the genome increase risk of bipolar disorder. Mol Psychiatry. 2009 Apr. 14(4):376-80. [Medline].
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8. Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr, et al. Chromosome
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Handout: Lecture Prof. Dr. Dr. Mller

Depression: Practice Essentials, Background, Pathophysiology

Signs and symptoms

Depression: Practice Essentials, Background, Pathophysiology

Selective serotonin reuptake inhibitors (SSRIs)

Interpersonal psychotherapy (IPT)

Evidence-based psychotherapeutic treatments for children and adolescents with

Need for a rapid antidepressant response

Depression: Practice Essentials, Background, Pathophysiology

Depression: Practice Essentials, Background, Pathophysiology

An integrative model of late-onset depression posits that age-related brain changes

Depression: Practice Essentials, Background, Pathophysiology

Some evidence suggests that late-onset depression (after age 60 years) is an

Impaired social supports

Cognitive-behavioral models of depression suggest that the presence of negative life

Depression: Practice Essentials, Background, Pathophysiology

Neuroendocrine abnormalities and neurodegenerative diseases

Depression: Practice Essentials, Background, Pathophysiology

Children and adolescents

Recurrence of early depression

Diagnosis of major depression

Depression Treatment & Management: Approach Considerations, Pharmacologic The...

Depression Treatment & Management

Pharmacologic Therapy for Depression

Selective serotonin reuptake inhibitors (SSRIs)

Depression Treatment & Management: Approach Considerations, Pharmacologic The...

Selective serotonin reuptake inhibitors

Serotonin/norepinephrine reuptake inhibitors

Serotonin-Dopamine Activity Modulators

Depression Treatment & Management: Approach Considerations, Pharmacologic The...

mixed episodes associated with bipolar I, as an adjunct to MDD, irritability

Monoamine oxidase inhibitors

St. John's wort

Comparative effectiveness of antidepressants

The AHRQ found that average effectiveness of those 12 antidepressants appeared

Antidepressant effectiveness and depression severity

Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...

Selective serotonin reuptake inhibitors (SSRIs)

Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...

Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine uptake, and

Venlafaxine (Effexor, Effexor XR)

Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...

Doxepin (Sinequan, Silenor)

Antidepressants, MAO Inhibitors

Selegiline transdermal patch (Emsam)

Lithium carbonate (Eskalith, Lithane, Lithobid)

Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...

treat or prevent episodes of depression. Lithium is contraindicated in patients with

Serotonin-Dopamine Activity Modulators

Aripiprazole (Abilify, Abilify Discmelt)

Mirtazapine (Remeron, Remeron SolTab)

Trazodone (Desyrel, Oleptro)

Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepress...

Liothyronine (Liothyronine T3, Cytomel)

Neurology & Psychiatry, Herbals

Hypericum perforatum (St John's Wort)