Psychatric disorders

DEPRESSION

1. Depressive disorders
a. Major depressive disorder (MDD): Unipolar disorder with somatic
and cognitive symptoms .
b. Dysthymic disorder: Chronic depressed mood occurring more days
than not for at least 2 years but does not meet the criteria for MDD
2. Bipolar disorders
a. Bipolar I (BP I): Chronic disorder marked by one or more manic or
mixed episodes +major depressive episodes
b. Bipolar II (BP II): Chronic disorder marked by one or more major
depressive episodes+ one hypomanic episode
c. Cyclothymic disorder: Several periods of hypomania and mild
depression, none of which meets the criteria for mania or major
depressive episode
Major Depressive Episodes and Disorder
Has the following criteria:
a. Depressed mood or marked decrease in interest/pleasure in usual
activities (must have one of these two symptoms) accompanied by
sleep disturbances, appetite changes, decreased energy, feelings of
guilt or worthlessness, psychomotor retardation/agitation, decreased
concentration, and suicidal ideation (five of nine symptoms total) for
at least 2 weeks

b. The presence of specific clinical features is only part of the MDD
diagnostic picture+The severity and duration of symptoms and the
patients change in level of function and interest in usual activities
Assessment of patients with MDD
a. Psychiatric history: A thorough history of symptoms is compared
with the diagnostic criteria, and the diagnosis is made on the basis of
collected data.
b. Clinician rating scales: psychometric instruments used to identify
depression and assess its severity.
- Hamilton Rating Scale for Depression (HAM-D)
-Quick Inventory of Depressive Symptoms (QIDS) clinician rated
(CR).
A response is usually defined as at least a 50% reduction in the HAM-
D score.
Remission is a return to a normal state or a HAM-D of 7 or less.
Scores from these scales are not required for the diagnosis, but the
HAM-D is a standard instrument used to show efficacy in clinical trials
for U.S. Food and Drug Administration (FDA) approval.
- Clinical Global Impression (CGI) scale is a clinician-rated scale that
evaluates the severity and improvement of patients overall. ---The
Montgomery-sberg Depression Rating Scale instrument that
evaluates symptoms of depression.
Patient rating scales: These are patient-completed rating
instruments. Answers to the questions are used to identify and assess
the level of depression.
The Beck Depression Inventory (BDI)
QIDS Self-Rated (SR) .
d. Physical examination and laboratory tests: rule out physical
causes (e.g., thyroid disorders, vitamin deficiencies) that may mimic
symptoms of depression.
e. Biologic testing: Depression is commonly associated with
abnormalities in the dexamethasone suppression test and tests of the
thyroid axis. However, these tests are not routinely used in clinical
practice.
f. Medications and substances (e.g., interferons, benzodiazepines,
barbiturates, alcohol, central nervous system depressants, lipid-
soluble -blockers, withdrawal from stimulants, cocaine,
amphetamines) can have depression as an adverse effect.
Pharmacists should perform a drug and substance use review to
identify possible causes.
Therapeutic Options
1. Psychotherapy and exercise: Examples include interpersonal
psychotherapy and cognitive-behavioral therapy.
Takes longer to observe effectiveness, but when combined with
pharmacotherapy, it is effective. Psychotherapy is recommended as
monotherapy as initial treatment
in patients with mild to moderate MDD (cognitive-behavioral and
interpersonal therapy have best evidence.
2. Pharmacotherapy: Drug therapy may lead to a more rapid
response than psychotherapy, but when discontinued, there is a risk
of relapse and adverse effects.
3. Electroconvulsive therapy (ECT): Option for refractory depression,
depression in pregnancy, psychotic depression, and other conditions
for which medications may not be optimal or effective.
The usual cycle is three treatments per week. Temporary memory
loss is common, and medications that affect seizure threshold must
be withdrawn before treatment. Electroconvulsive therapy has also
been recently suggested as initial treatment if symptoms are severe
or life threatening
Pharmacotherapeutic Options:
1. Selection: Consider possible drug-drug and drug-disease
interactions, concurrent illnesses, prior responses, family members
prior responses, patient preference, and cost.
2. Onset: it takes 46 weeks to see the full effect of antidepressants,
but it may take as long as 68 weeks to see a response. Remission
may take up to12 weeks. Some symptoms (e.g., sleep disturbances)
may show improvement in 12 weeks.
3. Adequate trial: An adequate trial includes the correct drug for the
patient and a therapeutic dose for an appropriate duration. A
therapeutic trial ranges from 4 to 8 weeks
4. Response and remission: A response is usually defined as a 50%
reduction in symptoms. Remission is a return to normal mood (e.g.,
HAM-D of 7 or less). Optimizing the dose and/or duration is
important for achieving remission.
5. Efficacy of antidepressants according to rigorous clinical trials is
about 60%70% in response regardless of drug. Effectiveness, which
is more reflective of clinical practice, is lowerabout 50%
60 .%The remission rate with one antidepressant is about 30%, seen
in the recent STAR*D trial when the first drug is initiated.
6. .Drug interactions : Many antidepressants inhibit cytochrome
P450 (CYP) enzymes.

A. Tricyclic Antidepressants
1. Tricyclic antidepressants (TCAs) were the first antidepressants
available.
off-label uses : treatment for pain syndromes, migraine prophylaxis,
and anxiety disorders.
They are effective, but adverse effects have limited their use. Now
that newer agents with more tolerable adverse effect profiles are
available, these agents are used less often.
MOA:


They block the reuptake of 5-HT (serotonin) and norepinephrine
(NE).
The tertiary amines are more potent for NE uptake and are
metabolized to active secondary amines.
Also TCAs have -adrenergic blockade, antihistaminic effects, and
anticholinergic effects, leading to orthostasis, sedation, and
anticholinergic symptoms. They also lead to cardiotoxic effects (Table
2).

Cautions: patients with cardiac disease or seizure disorders. Patients
at risk of orthostatic hypotension are at increased risk of falls if they
take these agents
advantage : is that therapeutic serum concentrations can be
measured confirm adherence or toxicity.
A withdrawal syndrome that includes gastrointestinal (GI)
complaints, dizziness, insomnia, and restlessness occurs if these
drugs are discontinued too quickly. Gradual dose reductions help
reduce these symptoms.
B. Monoamine Oxidase Inhibitors
MOA: block the enzyme responsible for the breakdown of certain
neurotransmitters, such as NE.
There are two forms of this enzyme (MAO-A and MAO-B), and drugs
can block one or both of them. They are effective antidepressants
and may be especially useful for atypical depression (hypersomnia,
hyperphagia, and mood reactivity).
2. Nonselective drugs (phenelzine and tranylcypromine) .
3. avoid foods high in tyramine (e.g., aged cheese, preserved meats)
hypertensive crisis.
Drug interactions with MAOIs decongestants, antidepressants,
stimulants, pressors, and others.
- switching a patient from another antidepressant to an MAOIwait 2
weeks after the antidepressant is discontinued before initiating the
MAOI (except for fluoxetine, in which case the waiting period should
be 56 weeks).
When a patient is changed from an MAOI to another antidepressant,
a 2-week washout period is usually adequate.
Selegiline (MAO-B inhibitor) is now available in a patch formulation
called Emsam for the treatment of depression. available in doses of 6
mg/24 hours, 9 mg/24 hours, and 12 mg/24 hours.
Once the dose reaches 9 mg/24 hours, an MAOI diet is required.
c. Selective Serotonin Reuptake Inhibitors
MOA: SSRIs selectively inhibit the reuptake of serotonin into the
presynaptic neuron+ desensitize the presynaptic serotonin
autoreceptor involved in the negative feedback loop that normally
inhibits serotonin release.- increased serotonin concentrations in
the synapse.
-Blockade of serotonin reuptake increase in serotonin overall and
may influence all subtypes of serotonin receptors (serotonin 2A,
serotonin 2C, serotonin 3, and serotonin 4) unwanted adverse
effects (e.g., insomnia, restlessness, GI complaints).
The FDA has approved six SSRIs for the treatment of depression:
fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and
vilazodone.
Vilazodone (Viibryd) is an SSRI and a partial agonist at the serotonin
1A receptor.
Fluvoxamine is indicated only for obsessive-compulsive disorder but
is an effective antidepressant. Table 3 compares these agents.

2. The efficacy of SSRIs is equal for treatment of depression.
There are slight differences in adverse effect profiles, and patients
may tolerate one better than another.
The STAR*D (Sequenced Treatment Alternatives to Relieve
Depression) trial showed that patients who do not respond to one
SSRI may respond to another.
Adverse effects: Activation, agitation, anxiety, or panic may be
especially during the early phase of therapy.
The most common adverse effects associated with this class of agents
include GI complaints, insomnia, restlessness, headache, and sexual
dysfunction.
the most activating SSRIs are fluoxetine and vilazodone,
whereas paroxetine and fluvoxamine are the most sedating.
Sertraline, citalopram, and escitalopram do not have
appreciable sedating or activating effects.
Sexual dysfunction is more common than reported in the
prescribing information wait-and-see method, adding
bupropion for the treatment of sexual dysfunction, lowering
the dose of the SSRI, or adding an agent such as sildenafil or
cyproheptadine or changing to a drug less likely to cause this
problem is also reasonable.
4. Because these drugs have such potent serotonergic activity,
combinations with other drugs affecting serotonin can lead to
serotonin syndrome. Examples include MAOIs, dextromethorphan,
meperidine, sympathomimetics, triptans, lithium, TCAs, and
serotonin norepinephrine reuptake inhibitors (SNRIs).
Serotonin syndrome : hypomania, restlessness, myoclonus,
hyperreflexia, diaphoresis, shivering, tremor, diarrhea, and
incoordination. It can be, and has been, confused with neuroleptic
malignant syndrome.
Treatment : discontinuing the offending agent; providing supportive
measures such as cooling blankets and respiratory assistance; and
providing clonazepam for myoclonus, anticonvulsants for seizures,
and nifedipine for hypertension.
extrapyramidal symptoms (EPS), including akathisia, dystonia, and
bradykinesia, but these are not common effect on dopaminergic
neurotransmission in the basal ganglia.
6. withdrawal syndrome especially for the drugs with shorter half-
lives, so a gradual dose reduction (e.g., over 24 weeks) may be
indicated.
It is manifested as GI complaints, headache, dizziness, impaired
concentration, flulike symptoms, anxiety, and insomnia. If the
problem is severe or persists the drug can be reinitiated and the
dose gradually reduced again most common with paroxetine, less
so with sertraline, and even less likely with fluoxetine.
7. the risk of QT prolongation with citalopram at doses higher than
40 mg/day.
Patients who have risk factors for QT prolongation (congenital long
QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent
acute myocardial infarction, uncompensated heart failure,some
medications) should not be treated with citalopram Doses of
citalopram should be lowered to 40 mg/day in patients who are
receiving higher dosages unless the benefits significantly outweigh
the risks.
The maximal recommended dose of citalopram is 20 mg/day for
patients with hepatic impairment, patients who are older than 60
years, patients who are CYP2C19 poor metabolizers, or patients who
are taking concomitant cimetidine or another CYP2C19 inhibitor.
Adv: The low cost and better tolerability of SSRIs warrant them as
first-line treatment of MDD in most patients.
9. Prozac Weekly (90 mg) can be taken once weekly. It is taken only
during continuation therapy rather than as initial treatment.
Paroxetine controlled release (Paxil CR) is now also available and may
have slightly better tolerability than regular paroxetine. However,
both products are administered once daily, and there appears to be
no difference in efficacy. The weekly and CR products are also higher
in cost.
10. Escitalopram is the S-isomer of citalopram. It is the active
component of the racemic mixture. At a 10- mg dose, it is as effective
as citalopram 20 mg (or 40 mg as described in prescribing
information), but at this dose, there are fewer adverse effects. At
higher doses, this advantage is not as pronounced.
D. Serotonin Norepinephrine Reuptake Inhibitors
Agents: Venlafaxine, desvenlafaxine, and duloxetine.
MOA: block the reuptake of NE and serotonin. Unlike TCAs, they have
negligible effects at other receptors that cause anticholinergic or
antihistaminic adverse effects(except duloxetine, which appears to
have a slightly higher incidence of anticholinergic symptoms.)
Venlafaxine has a dose-related effect on NE compared with
desvenlafaxine and duloxetine.
At doses below 150 mg/day, venlafaxine has primarily a serotonin
effect.
2. Whether the dual action of venlafaxine makes it more effective
than SSRIs is an area of continued research. There appear to be
patients (e.g., treatment nonresponders) who benefit either from
agents that affect NE and serotonin or from combinations of drugs
with that effect.
3. adverse effect of venlafaxine is similar to that of the SSRIs, with GI
complaints being common+ increases in blood pressure(mild unless
the patient already has hypertension that is not well controlled). It is
a dose-related phenomenon as described earlier.
All the SNRIs may produce neuroleptic malignant syndrome or
serotonin syndrome.
In overdose situations, venlafaxine versus SSRIs has been associated
with increased rates of death. The risk of suicide completion with
SNRIs is still lower than with TCAs.
4. Duloxetine has also been approved for the treatment of diabetic
peripheral neuropathy, fibromyalgia, and chronic musculoskeletal
pain caused by chronic lower back pain or osteoarthritis pain Be
careful when using this drug with inhibitors of CYP2D6.
Monitor blood pressure because increases have been observed.
This drug can cause liver toxicity and should not be used in patients
with hepatic insufficiency, end-stage renal disease requiring dialysis,
or severe renal impairment.
5. Abrupt discontinuation of venlafaxine can lead to a withdrawal
syndrome similar to that seen with the SSRIs.
- Desvenlafaxine (Pristiq) is an active metabolite of venlafaxine.
Whether it has any advantage over the parent compound is
controversial.
E-Miscellaneous:
I. Trazodone
1. This drug is SSRI+ blocks serotonin 2A receptors.
It does not cause anticholinergic or cardiotoxic effects like the TCAs,
but it still causes orthostatic hypotension and sedation.
2. Because of its sedative properties, trazodone is now often used for
insomnia.
3. It is important to be aware of the potential for priapism, even
though it is rare (0.1% or less).
II. Nefazodone

1.. SNRI+ serotonin 2A antagonist
Some have referred to this class as serotonin antagonist reuptake
inhibitors (serotonin 2A antagonist/reuptake inhibitors).
Unlike trazodone, it causes minimal effects on sexual function and is
less likely to cause orthostatic hypotension.
3. Some data suggest that the serotonin 2Ablocking activity makes
this drug more effective for anxiety associated with depression.
4. The short half-life makes it necessary to administer doses two
times/day.
Adverse effects sedation, GI complaints, dry mouth, constipation,
confusion, and light-headedness.
DI: it is a potent inhibitor of CYP3A4, caution is necessary when using
it concomitantly with drugs metabolized by this system.
7. Because of the potential for liver toxicity and the black box
warning, nefazodone is now considered a second- or third-line agent.
Liver function tests must be monitored if nefazodone is used.
III. Bupropion
MOA: This drug is primarily an inhibitor of dopamine and NE reuptake
(at high doses), with minimal effects on serotonin.
The parent drug blocks dopamine reuptake, whereas the
metabolite blocks NE reuptake.
Adverse effect:
1. Increased risk of seizures. This risk can be minimized by avoiding
use in susceptible patients (e.g., history of seizure disorder, eating
disorders) by not giving more than 150 mg/dose or 450 mg/day
(immediate release), 400 mg/day (sustained release), or 450 mg/ day
(extended release); and by avoiding rapid dosage titration every few
days.
The sustained-release and extended-release products may also cause
fewer adverse effects; they have largely replaced the immediate-
release tablets.
2. The most common adverse effects : insomnia, anxiety, irritability,
headache, and decreased appetite.
3. increase energy and cause psychosis.
The drug may actually improve sexual function; thus, it may be
useful in patients not tolerating other agents for this reason.
Bupropion has also been used for attention-deficit/hyperactivity
disorder and may help with concentration.
4. Recently, the FDA determined that Budeprion XL 300 mg
(bupropion hydrochloride extended-release tablets), manufactured
by Impax Laboratories (marketed by Teva Pharmaceuticals USA), was
not therapeutically equivalent to Wellbutrin XL 300 mg (does not
affect 150-mg tablets). The bioequivalence studies determined that
Budeprion XL 300-mg tablets failed to release bupropion into the
blood at the same rate and to the same extent as Wellbutrin XL 300
mg, therefore leading to reduced efficacy. This product has been
removed from the market.
III. Mirtazapine
MOA: antagonist of presynaptic 2-autoreceptors and
heteroreceptors increase in NE and serotonin in the synapse. In
addition, the drug blocks serotonin 2A (resulting in no sexual
dysfunction, no anxiety, and sedation), serotonin 3 (no nausea and no
GI disturbances), and serotonin 2C (weight gain) receptors.
2. Although the drug is better tolerated than the TCAs, it still has a
pronounced sedative effect, together with increased appetite, weight
gain, constipation, and asthenia.
Abnormal liver function tests
very small risk of neutropenia or agranulocytosis.
Lower doses may be sedating, whereas higher doses may cause
insomnia.
Antidepressants and Suicidality: High incednce in children,
adolescents, and young adults (up to 24 years of age), resulted in a
black box warning for all antidepressants inclusive of both older and
newer agents.
Monitor patients, especially children and adolescents, for treatment
failure or worsening symptoms of depression when these drugs are
initiated or the dose is increased.
Other signs to watch for include suicidal ideation, agitation and
anxiety (activation syndrome), and other symptoms that are unlike
the presenting symptoms of depression in the patient
Initiating, Adjusting and Monitoring Therapy
1. There are three phases of therapy:
a. Short term (acute): The goal of this phase is to resolve symptoms,
which usually takes 612 weeks.
b. Continuation: The goal of this phase is to keep the symptoms in
remission by using full-dose therapy. This phase usually continues for
49 additional months to keep the patient in remission.
c. Maintenance: Long-term therapy at full doses may be required in
patients at high risk of relapse, which would include prior episodes of
depression or a strong family history of relapse. The duration of this
phase is determined on an individual basis.
full therapeutic doses should be givenfor 68 weeks andfor up to 12
weeks. If there is no response medication failure.-try another
class( some patients who do not respond to one SSRI may respond to
another).
Treatment resistance when two or more agents from different
classes have been tried ECT, augmentation therapy, or
combination therapy if they have not been used already.
Patients should be monitored for response through interviews
and/or by repeating rating scales+monitor for adverse effects.
N.Bmost of the adverse effects are not life threatening, they do have
an important effect on adherence.
The FDA has required that package labels for antidepressants include
a statement to monitor patients for emerging suicidal thoughts and
behaviors and continuing depressed mood, especially when
antidepressants are initiated.
Antidepressant Combination Therapy
1. Affect different systems selectively. It is now possible to affect
serotonin, NE, and dopamine differentially.(esp in treatment
resistant cases)
2. The use of combinations with lower doses of each may lead to
fewer adverse effects.
3. Using a second antidepressant may offset an adverse effect of
another (e.g., using trazodone to treat SSRI-induced insomnia).
4. Adding bupropion to existing SSRI therapy is a strategy for patients
who do not fully respond to the SSRI alone.
Augmentation Therapy
1. Patients not responding adequately have been successfully treated
when non-antidepressant drugs are added to augment existing
antidepressant therapy.
2. Augmentation regimens include the following:
a. Lithium: Adding lithium appears to help in treatment-resistant
depression. The dosing is controversial, ranging from full doses to
concentrations used for bipolar disorder to small doses.
b. Thyroid: Adding thyroid is also effective for treatment-resistant
depression. The effect is not dependent on thyroid dysfunction. T3
appears more effective than T4. The usual dose is 25 mcg/ day.
c. Buspirone has also been used as an augmenting agent.
d. Second-generation antipsychotics (SGAs or atypical
antipsychotics)
Almost all of them have been used, but only aripiprazole and
Seroquel XR have received FDA-labeled approval for this indication.
Olanzapine in combination with fluoxetine is also approved for
treatment-resistant depression.
Treatment Algorithms
a. All patients were initially treated with citalopram monotherapy,
and only about 30% achieved remission.
b. If remission not achieveda switch strategy or augmentation
strategy - bupropion, sertraline, venlafaxine, or cognitive therapy.
slightly higher rates of remission with augmentation.
Bupropion and buspirone augmentation worked similarly, and the
former agent was better tolerated- if not responding change to
mirtazapine or nortriptyline or to have augmentation with lithium or
thyroid(there were not many differences). Thyroid augmentation
worked as well as lithium.
d. Remission rates decreased at each level of treatment. Although
data from this trial will continue to be analyzed, the results suggest
that:
(1) less than one-third of patients achieve remission with initial SSRI
monotherapy
(2) switching or augmentation strategies are viable options, with no
marked increase in efficacy with either strategy.
(3) Switching antidepressants may be a good option for patients who
either do not respond to or do not tolerate a drug, and augmentation
may be good for partial responders. However, continued monitoring
of these observations is necessary to confirm these results.
II. BIPOLAR DISORDER
A. Overview of Bipolar Disorder
Bipolar disorder + manic episode.
Mania : affective opposite of depression.
A manic episode is characterized by at least 1 week of an abnormal
and persistently elevated mood.
Other symptoms include inflated self-esteem, irritability, decreased
need for sleep,pressured speech, flight of ideas, poor attention,
increased hyperactivity or agitation, and involvement in high-risk,
pleasurable activities without respect to the consequences.
Two types of bipolar disorder:
a. Bipolar I: Presence of manic episodes and major depressive
episodes
b. Bipolar II: Presence of major depressive episodes and hypomanic
episodes
Lithium for Bipolar Disorders
MOA:
include attenuation of dopamine function; facilitation of -
aminobutyric acid (GABA) function; and alteration of serotonin
function, such as improvement in serotonin 1A and reduction in
serotonin 2 neurotransmission.
Indications: Manage manic and depressive components. Although it
is not a particularly good antidepressant as monotherapy in unipolar
depression, it is effective in patients with bipolar disorder.
Tips:. It takes about 12 weeks to see the full effects of lithium, so
most clinicians use antipsychotics and/or benzodiazepines as
adjunctive therapy during this period to cover the agitation and other
symptoms.
Pharmacokinetics: (1) Its half-life is 2024 hours. (2) It is excreted
95% unchanged by glomerular filtration, and anything that alters
glomerular filtration rate affects its clearance. (3) Pharmacokinetic
methods are available for early prediction of doses, but waiting 56
days for steady state seems to work just as well.
Dosing: Initial dosing is in the range of 600900 mg/day in divided
doses and then titrated upward on the basis of response and
tolerability.
Maintenance doses are based on serum concentrations, symptom
relief, and the occurrence of adverse effects.
Follow up:. A pre-lithium workup includes a complete blood cell
count, electrolytes, renal function, thyroid function tests, urinalysis,
electrocardiogram (ECG), and pregnancy test for women of
childbearing age.
Perform renal function tests, thyroid function tests, and a urinalysis
every 612 months
Monitoring: Serum concentrations must be monitored. The half-life is
about 1 day, so steady state occurs in about 5 days. Even though it is
not steady state, it may be prudent to obtain a serum concentration
3 days after dosage changes.
Target concentrations: 0.81.2 mEq/L in acute mania and 0.61.0
mEq/L during maintenance.
Concentration-response data are based on 12-hour postdose
concentrations.
Adverse effects are common with lithium esp during therapy
initiation or after dose changes.

Toxicity: lethargy, coarse tremor, confusion, seizures, and coma and
may even result in death.
Lithium level as well as sodium/renal function should be drawn so
that lithium levels can be accurately estimated.

Situations to consider during lithium therapy are listed in Table 5.

Anticonvulsants for Bipolar Disorder: These are also considered
mood-stabilizing drugs reduce manic and depressive episodes.
1. Divalproex: It is as effective as lithium in acute and prophylactic
management. It appears to be good for rapid cyclers but may not
as effective during depressive episodes.
Target serum concentrations range from 50 to 125 mcg/mL.
checked 35 days after initiation or after a change of dose.
Hypoalbuminemia increases the risk of increased free
concentrations.
Liver toxicity is a risk but mostly in young childrenthose with
metabolic diseases or those taking several medications.
If tolerated, the level may be pushed upward in the range.
Nonresponse to treatment is common if the dose is too low;
however, the free fraction increases as the serum concentration is
increased. More adverse effects may be seen as the dose is
increased because the percent unbound increases as total
concentrations reach 100125 mcg/mL. Adverse effects (e.g.,
neurotoxicity, sedation, hair loss, thrombocytopenia) are
increased at concentrations greater than 80 mcg/mL. The
extended-release product has lower bioavailability than the
enteric-coated preparation (8%20%) and should be accounted
for when converting between the two.
2. Carbamazepine: This drug also appears effective for acute mania
and maintenance therapy.
Equetro was recently approved by the FDA for acute manic/mixed
episodes.
Carbamazepine is also used for long-term management.
Although the same serum concentration range as for seizures (412
mcg/ mL) should be used, keep in mind that clinicians may push it
higher on the basis of tolerability and effect.
potential drug interactions:Auto-induction . It can auto-induce its
own metabolism, and this effect appears to be complete about 4
weeks after each dose adjustment.
Monitoring: complete blood cell count, liver function, and serum
sodium.
Carbamazepine can also be added to lithium for patients who have
not responded to monotherapy.- The patients sodium
concentrations must be monitored for both carbamazepine and
oxcarbazepine.--> Hyponatremia can occur, and the drug should be
discontinued if sodium concentrations fall below 130 mEq/L.
3. Lamotrigine: This drug has been approved for maintenance
therapy.
It appears to be effective, particularly when the patient presents
during the depressed phase.
SE:1.Rashesinvolvement of mucosal membranes (i.e., eyes, nose,
and mouth) requires immediate medical attention.
a. Remember to start with lower doses and to correct the dosing
schedule if valproic acid is also used because of a drug interaction.
Titration period is lengthy, so onset of therapeutic effect can be
delayed.
b. Rash occurs in about 0.3% of adults; discontinue agent if rash is
observed. Rash occurs in about 1% of children. Risk factors include
concurrent use of valproic acid, younger age, and high doses or rapid
dosage titration.
The onset of rash is most often noted during the first 28 weeks of
therapy and may also present as a Stevens-Johnson syndrome rash.
2. Aseptic meningitis in adult and pediatric patients, and patients
who experience headache, fever, chills, nausea, vomiting, stiff neck,
rash, abnormal sensitivity to light, drowsiness, or confusion while
taking the drug should contact their health care professional right
away. In 15 of 40 identified cases of aseptic meningitis, symptoms
returned when rechallenged with lamotrigine. Symptoms have
occurred 142 days after starting the drug, and many of the cases
required hospitalization.

DI:
Inducers:Carbamazepine, oral contraceptives, primidone,
phenobarbital, and phenytoin
4. Topiramate is also being used for bipolar disorder, but
comparative data with other anticonvulsants are unavailable.
Antipsychotics for Bipolar Disorder:
Fast-acting agents can be given as adjunctive therapy acutely while
waiting for the mood stabilizer to take effect or as monotherapy for
the acute episode.
These drugs help with agitation and overactivity and appear to have
mood-stabilizing properties.
They may be beneficial for those who are psychotic, aggressive, or
highly irritated.
Clinicians will often combine one of these drugs with a traditional
mood stabilizer for severe symptoms.
All atypical antipsychotics have received approval for use in acute
mania or mixed episodes except for clozapine.
Quetiapine XR has received approval for use in acute bipolar
depression as well as in bipolar maintenance as an add-on treatment.
Olanzapine and aripiprazole have been approved for use in bipolar
maintenance as monotherapy.
Metabolic adverse effects associated with antipsychotic use should
be considered when medications are administered long term
E. Benzodiazepines for Bipolar Disorder:
These agents are acutely helpful for agitation but are not as helpful
for the core symptoms, nor do they prevent relapses.
They are particularly useful for insomnia, hyperactivity, and
agitation.
Lorazepam or diazepam is often used in the acute setting, but long-
term therapy is not recommended.
III. SCHIZOPHRENIA
A. Characteristics
Schizophrenia is a thought disorder characterized by a mix of
symptoms. These symptoms can involve
perception (e.g., hallucinations), ideation, reality (e.g., delusions),
cognition (e.g., loose associations,)emotions (e.g., flat affect),
behavior (e.g., disorganization), attention, concentration, motivation
(e.g avolition), and judgment.
Usually, symptoms are divided into
positive and negative. However, other domains have also been
suggested.
.

3. Types of schizophrenia
a. Paranoid: Prominent preoccupation with delusions and
hallucinations
b. Disorganized: Disorganized speech and behavior and/or flat or
inappropriate affect
c. Catatonic: Prominent motor symptoms with nonreactivity to the
environment
d. Undifferentiated: No clear prominence of a particular
constellation of symptoms
e. Residual: Absence of prominent symptoms but ongoing
disturbance of less magnitude
4. Some Definitions:
a. Delusions: These are erroneous beliefs involving
misinterpretations of reality and are relatively resistant to evidence
that refutes them. A fixed delusion will not change, no matter how
much evidence offered to the contrary.
b. Hallucinations: These perceptual abnormalities can involve any
sensory system. With schizophrenia, auditory hallucinations are most
common. These can be persecutory (e.g., someone is going to get
me), paranoid (e.g., someone is watching), or command (e.g.,
someone told me to do it).
c. Thought disorder: This is manifested in several ways. Loose
associations refers to the person going from one topic to another as
though the topics were connected. Tangential speech refers to
answers to questions that are only slightly related or totally unrelated
to the question. Word salad refers to speech that is almost
incomprehensible and is very much like receptive aphasia.
Course of Illness
1. Onset is usually between adolescence and early adulthood. It
occurs earlier in men (i.e., early 20s) than in women (i.e., late 20s to
early 30s). The incidence is about equal between sexes.
2. Most patients fluctuate between acute episodes and remission.
Periods between episodes may include some residual symptoms.
3. There are four phases of schizophrenia
a. Prodromal phase: This phase is characterized by the gradual
development of symptoms that may go unnoticed until a major
symptom occurs. It may include isolation, deterioration of hygiene,
loss of interest in work or school, and dysphoria.
b. Acute phase: This is the full-blown episode of psychotic behavior.
People may be unable to care for themselves during this phase.
c. Stabilization phase: The acute symptoms begin to decrease, and
this phase may last for several months.
d. Stable phase: During this phase, symptoms have markedly
declined and may not be present. Nonpsychotic symptoms such as
anxiety and depression may be present.
NB: Complete remissions without symptoms are uncommon.
Causes
1.The causes of schizophrenia are unknown. It appears to involve
neurophysiological and psychological abnormalities.
2. The primary neurotransmitters believed to be involved in the
etiology are dopamine and serotonin.
It does appear that in some areas of the brain, dopamine overactivity
results in some symptoms, whereas in others, underactivity may
occur.
Positron emission tomographic scanning shows areas of
hypermetabolism and hypometabolism.
Risk factors :
Family history
lower socioeconomic class
having a poor birth history
experiencing intrauterine trauma
living in an urban area
stress
being born during the winter.
Pharmacotherapy:
First-Generation Antipsychotics =FGAs= typical or conventional
antipsychotics
1. This class of agents includes all the older antipsychotic agents.
Chlorpromazine was the first agentused clinically.
2 .These agents can be categorized on the basis of chemical class or
potency.


Actions: anticholinergic, antihistaminic, and -adrenergic blocking
properties and tend to be worse with low-potency agents.
These drugs can also be categorized by potency as antagonists at
dopamine D2 receptors.
The high-potency agents at dopamine D2 have less potency at the
other receptors the adverse effect profiles differ also by potency.





Adverse effects:
Sedation: The degree of sedation depends on the drug. If sedation
occurs, it is usually worse initially and is then tolerated better with
time. It tends to be dose-related.
Anticholinergic effects: Dry mouth, constipation, blurred vision, and
urinary hesitancy can occur.if affect tolerability receive a high-
potency agent.
Antiadrenergic effects: The -adrenergic blocking effect is seen as
orthostatic hypotension. Patients who are predisposed to such
effects (e.g., patients who are elderly, dehydrated) should probably
receivea high-potency agent.
Extrapyramidal symptoms
a. Parkinsonism: symptoms such as bradykinesia, rigidity, tremor, or
akinesia.
It is usually responsive to anticholinergic agents such as
diphenhydramine, trihexyphenidyl, and benztropine.
b. Dystonia: Examples include torticollis, laryngospasm, and
oculogyric crisistreated with anticholinergics.
c. Akathisia: This is a somatic restlessness and inability to stay still or
calm. It may respond to anticholinergics, but it may be more
responsive to lipophilic (fat soluble) -blockers such as
propranolol.
d. Tardive dyskinesia: This is a result of long-term antipsychotic
therapy :
Diagnosed only after at least 6 months of exposure to
antipsychotics.
The risk of tardive dyskinesia with FGAs is MUCH GREATER
THAN with SGAs.
Tardive dyskinesia usually involves the jaw or oral musculature
and may be partly attributable to dopamine receptor
supersensitivity.
it can be difficult to treat, and in some patients (probably less
than one-half), it may not completely resolve when the drug is
discontinued.
The risk increases with continued exposure to the drug.
Decreasing the dose can help(risk of psychotic symptoms
rturn) an intervention may be necessary.
1-change to another antipsychotic (other antipsychotic have lower
potential for TD) Clozapine has not been associated with tardive
dyskinesia
2.Vitamin E supplementation.
N.B: Anticholinergic agents should not be given to treat tardive
dyskinesia worsen the symptoms.
Neuroleptic malignant syndrome: serious complication occurs
with all agents (more common with high-potency drugs).
Manifestation: agitation, confusion, changing levels of consciousness,
fever, tachycardia, labile blood pressure, and sweating. Its mortality
rate ishigh
Intervention:Discontinue the offending agent and give supportive
therapy+ fluids +cooling.
Bromocriptine and dantrolene have been used with varying success.
Endocrine effects: Galactorrhea and menstrual changes can occur
because of hyperprolactinemia caused by antipsychotics.
Dopamine blockers can increase prolactin concentrations
(hyperprolactinemia).
Atypical agents (particularly clozapine and olanzapine) have been
associated with new-onset diabetes mellitus and metabolic syndrome
Monitoring: weight, blood pressure, fasting glucose, lipids, and waist
circumference at baseline and periodically .
Weight gain: This occurs in up to 40% of patients, with low-potency
agents having higher risk.
Interventions: keeping the dose as low as possible and implementing
dietary management.
Weight gain may occur because of actions at histamine and/or
serotonin receptors.
Sexual dysfunction: Erectile problems occur in 23%54% of men.
Loss of libido and anorgasmia may occur in men and women.
Venous thromboembolism (VTE):
FGAs and SGAs were associated with increased risk of deep
VTE or pulmonary embolism
Second-generation antipsychotics >> risk of VTE than from
first-generation drugs (73% vs. 28%, respectively).
Miscellaneous:
Low-potency agents such as thioridazine and chlorpromazine
pigmentary deposits on the retina and corneal opacity.
Many of the typical agents can cause serious changes on the
ECG (e.g., prolongation of the QT interval). arrhythmias and
death.
Therapy initiation:
In the past, acute episodes were treated very aggressively with
high doses neuroleptization.
Because neuroleptization can lead to adverse effects start
with full therapeutic doses
. Dosing during the stabilization phase may be less aggressive,
but too low a dose increases the risk of relapse.
Administration route:
Oral therapy is most common
parenteral drugs can be used acutely if the patient does not
adhere to therapy or is agitated and will not take oral
medications. Haloperidol can be given intramuscularly.
Don't give IV haloperidol (has been linked to toxicity including
torsades de pointes).
Depot forms of haloperidol and fluphenazine are available,
providing sustained concentrations for about 1 month for
haloperidol and 23 weeks for fluphenazine- only for chronic
therapy in patients who have trouble adhering to oral therapy.
Fluphenazine decanoate requires bridging with oral therapy
when treatment is begun.
Therapy duration:
Continuation of therapy during the stable phase is of concern
because of the risk of adverse effects (e.g., the tardive
dyskinesia associated with the older agents). This is of less
concern with the newer drugs.
Relapse rates are more than 50% during the first year or so
after discontinuing these agents for both first-episode patients
and patients who relapsemaintain the antipsychotic at the
minimal effective dose continuously may be the best approach
for most patients.
Some first-episode patients may be tried off drugs after being
symptom free for 2 years.
Those with a history of episodes should probably be symptom
free for 5 years before discontinuation is considered.
Long-term therapy should include monitoring for metabolic
complications such as diabetes, weight gain, and lipid
abnormalities.
SGAs for Schizophrenia
Reduce EPS adverse effects and tardive dyskinesia and to improve
efficacy.
The characteristics that:
(1) the risk of EPS is lower than with typical antipsychotics at usual
clinical doses
(2) the risk of tardive dyskinesia is reduced
(3) the ability to block serotonin 2 receptors is present improve
activity for the negative symptoms of schizophrenia and reduce the
risk of EPS.
May be considered as the first line although of its high cost.

Clozapine (Clozaril):


MOA:less-potent dopamine blocker than typical antipsychotics +
serotonin 2 antagonist.
Actions: Possesses the ccc of SGAs
Effective for many patients who have not responded to typical
agents.( The only new agent with sufficient data at this time to
support this claim)
Affect brain regions selectively, particularly those that control
the cognitive and affective states altered in people with
schizophrenia (i.e., the mesolimbic A10 tract, but not the A9
tract that modulates movement).
Adverse effects have limited the use of this agent.
a. Agranulocytosis: This is manifested as a reduction in WBCs count
and it increases the risk of serious or fatal infections. It is
contraindicated if the white blood cell count is less than 3500
The incidence is about 1%2% and is highest during the first 46
months of therapy.
Monitoring: patients must have a weekly complete blood cell count
for 6 months and then every 2 weeks after that while taking the drug.
The frequency can be decreased to monthly after 1 year if the white
blood cell count is greater than 3500 and the absolute neutrophil
count is greater than 2000.
N.B:If the white blood cell count is significantly decreased during
therapy (less than 3000/mm3), the drug should be discontinued.
NB:Patients must be enrolled in a Clozaril registry program (Clozaril
National Registry, Teva Clozapine National Registry), which monitors
the reporting of absolute neutrophil and white blood cell counts.



b. Other adverse effects: weight gain, sedation, hypersalivation, rapid
heart rate, orthostatic hypotension, and fever.
N.B: the presence of fever the possibility of infection and
agranulocytosis.
Black box warnings for seizures (more frequent at higher doses)
and myocarditis, orthostatic hypotension, and respiratory arrest.
If the drug is discontinued for 48 hours or more, retitration is
required to avoid orthostatic hypotension.
4. Risperidone (Risperdal):
MOA: potent dopamine D2 antagonist and a serotonin 2 antagonist.
It has limited anticholinergic activity.
Actions: At doses of up to 6 mg/day, the incidence of EPS has been
no higher than with placebo in clinical studies but EPS is a dose-
related phenomenon may be seen in patients taking the drug even
at usual doses.
Patients often tolerate risperidone >> haloperidol.
It probably has no advantage in patients requiring high doses of
antipsychotics.
Adverse effects : sedation, orthostatic hypotension, weight gain,
sexual dysfunction, and hyperprolactinemia.
Formulations:
long-acting IM formulation (risperidone [Risperdal Consta]) is now
available that >> tolerated than the other intramuscular depot forms
of antipsychotics ( administered every 2 weeks)+ requires a 3-week
bridge therapy with oral risperidone.
It is generally used only after the patient is known to tolerate oral
therapy.
Paliperidone (Invega) is an active metabolite of risperidone.
Paliperidone palmitate is also available as a monthly depot injection.
As with long-acting risperidone, tolerability with oral therapy should
be established before starting it.
5. Olanzapine (Zyprexa):
This drug is structurally similar to clozapine and has a similar
pharmacology.
No agranulocytosis.
May affect only the A10 tract of the mesolimbic system.
In one study, negative symptoms responded better than with
haloperidol.
Very low incidence of EPS(may appear at high doses).
Indication: treatment-resistant depression remains to be
determined.
Adverse effect: sedation, hypotension, and weight gain.
Formulations:
1.short-acting parenteral formulation for the rapid treatment of
agitation
2. long-action formulation for maintenance (Zyprexa Relprevv) given
every 24 weeks, depending on dose.
Black box warning postinjection delirium/sedation syndrome and
increased mortality in elderly patients with dementia-related
psychosis.
The drug can only be administered in registered facilities, and
patients need to be monitored for at least 3 hours postdose.
Quetiapine (Seroquel): low incidence of EPS.
preferred antipsychotic if psychosis occurs in a patient with
Parkinson disease.
Ziprasidone (Geodon):
less weight gain than other atypical antipsychotic agents.
Increase the QT interval on the ECG Use caution if combining
it with other drugs (e.g., TCAs or antiarrhythmics) that can also
increase the QT interval ventricular arrhythmias including
torsades de pointes syndrome.
The risk appears highest with thioridazine, clozapine,
ziprasidone, and iloperidone, although the other agents may
do this to a lesser extent.
Assess for the predisposing risk factors: as preexisting ECG
abnormalities, electrolyte disturbances, and concurrent
therapy with other drugs that prolong the QT interval.
It is now available in a parenteral formulation for acute
agitation.
The drug must be taken with food to increase absorption.
Aripiprazole (Abilify):
MOA: dopamine D2/serotonin 1 partial agonist and a serotonin 2
antagonist( sometimes referred to as a dopamine-serotonin
stabilizing agent).
low risk of EPS and tardive dyskinesia.
Adverse effect: headache, anxiety, insomnia, GI complaints,
somnolence, akathisia, constipation, and weight gain.
Asenapine (Saphris)
new atypical antipsychotic (2009) approved for schizophrenia and
acute manic and mixed episodes of bipolar I disorder (sublingual
formulation).
lower risk of metabolic effects and EPS but associated with a
high risk of orthostasis and sedation.
risk of hypersensitivity reactions
Iloperidone (Fanapt) new SGA that lower risk of metabolic effects.
+ lower risk of EPS, anticholinergic symptoms, and sedation but a
higher risk of orthostasis.
QT prolongation similar to that of haloperidol and ziprasidone.
Lurasidone (Latuda) is the newest antipsychotic (2010) on the market
that resembles other recent approvals.
It has a low risk of metabolic and cardiac effects together with a low
EPS risk.
MOA: potent antagonistic activity at serotonin 7 and a high affinity to
serotonin 1A receptors, which is theorized to have beneficial
cognitive and anxiolytic effects.
Dosing:The maximal daily dose has recently been increased to 160
mg/day and should be taken with food.
The recommended starting dose for moderate and severe renal
impairment and when used with a moderate CYP3A4 inhibitor (e.g.,
diltiazem) is 20 mg, and the maximal dose is 80 mg.
The recommended starting dose for moderate and severe hepatic
impairment is 20 mg, and the maximal dose is 80 mg in moderate
hepatic impairment and 40 mg in severe hepatic impairment.


Adjunctive Medications
1. Lithium: This agent may augment antipsychotic action.
2. Anticonvulsants (carbamazepine and valproic acid): may augment
antipsychotics, but their role in therapy remains undetermined. They
may be useful in patients with agitated or violent behavior.
3. Benzodiazepines: may be useful during the acute phase for
agitation or anxiety, but they are less effective for treatment of
psychotic symptoms.
These drugs must also be used with caution in patients with
schizophrenia because this population is at high risk of substance
abuse.
Comparisons of Typical and Atypical Agents:
1. 2
nd
Vs 1
st
generation antipsychotics: higher tolerability recommend
its use as a 1
st
line (they have close efficacy).
2. The Clinical Antipsychotic Trials of Intervention Effectiveness study
(CATIE, sponsored by NIMH) compared several SGAs with the older
agent perphenazine. Here are some of the findings:
a. Discontinuation
i. High in all groups: 74% of all patients discontinued before 18
months
ii. Olanzapine = 64%
iii. Perphenazine = 75%
iv. Quetiapine = 82%
v. Risperidone = 74%
vi. Ziprasidone = 79%
b. Time to discontinuation
i. All causes: Longest for olanzapine (significantly longer than for
quetiapine and risperidone, not the others)
ii. Lack of efficacy: Longest for olanzapine (significantly longer than
perphenazine, quetiapine, and risperidone, but not ziprasidone)
c. Duration of successful treatment: Longest for olanzapine
(significantly longer than for quetiapine, risperidone, and
perphenazine, as well as for risperidone compared with quetiapine)
d. Efficacy: Positive and Negative Syndrome Scale (PANSS) scores
i. Scores improved in all groups as time progressed.
ii. Initially, more improvement with olanzapine, but improvement
diminished with time
Adverse drug reactions
Olanzapine: More often associated with weight gain and metabolic
adverse effects
Perphenazine: More often associated with EPS
Meta-analyses:
1.analysis of FGAs and SGAs :clozapine, risperidone, and olanzapine
were more effective than the FGAs evaluated. Other SGAs were not
superior to FGAs.
2.2
nd
meta-analysis SGAs were compared for the change in total
PANSS score Olanzapine was significantly more efficacious than
aripiprazole (p=0.002), quetiapine (p<0.001), risperidone (p=0.006),
and ziprasidone (p<0.001). Most of the efficacy differences were
caused by improvement in positive, not negative, symptoms.
ANXIETY DISORDERS

Overview :
characterized by 6 months or more of excessive worry or anxiety,
generally with an unidentified cause.
Panic disorder is characterized by discrete periods of sudden, intense
fear or terror and feelings of impending doom. Usually, the
precipitating cause is unknown, but the patient can become
conditioned to believe it is attributable to some environmental cause.
This can lead to agoraphobiathe fear or avoidance of certain
situations (e.g., going to the mall or grocery store)because of the
belief that he or she will have one of these attacks.
Obsessive-compulsive disorder is characterized by obsessive or
intrusive thoughts that cannot be controlled and that are repetitive.
Compulsions are ritualistic behaviors (e.g., washing the hands,
combing the hair, cleaning the house.
Posttraumatic stress disorder follows a traumatic event. It is
characterized by increased arousal and avoidance of stimuli that
approximate the original traumatic event.
Social anxiety disorder is characterized by marked and persistent fear
and anxiety in social or performance situations that are recognized as
excessive or unreasonable. These situations are either avoided or
endured with intense anxiety.
Specific phobias characterized by intense fear or anxiety induced by a
specific object.
Pharmacotherapeutic Options for Anxiety Disorders
I.Benzodiazepines: have anxiolytic properties, and some have
preventive efficacy for panic attacks.
Adv:. highpotency,short half-life agents are the most rapidly
acting.
Pharmacologically, they share, to various degrees, five properties:
(1) anxiolytic, (2) hypnotic, (3(muscle relaxation, (4) anticonvulsant,
and (5) amnesic actions.
Tolerance of the anxiolytic action is uncommon.
Classification:Benzodiazepines are differentiated by their half-life
(plus or minus active metabolites and potency). If they are thought of
as short half-life/high-potency versus long half-life/lowerpotency
drugs, the following distinctions can be made:
i. Short half-life/high potency: These are usually more rapid-
acting agents that provide quicker control of the symptoms.
Disadv: tolerance of the hypnotic effect develops rapidly,
withdrawal problems are common, and interdose breakthrough
symptoms can occur.
Indications: used for acute management and later replaced
with longer half-life agents.
ii. Long half-life/low potency:
Adv:These drugs produce longer-lasting effects throughout the
day( withdrawal symptoms may be less pronounced).
Interdose breakthrough symptoms are less likely; however,
more hangover symptoms occur in the morning.
Disadv: These agents can accumulate in elderly patients.
.

Problems associated with benzodiazepines
1.Tolerance of thehypnotic actions occurs within days.
2. Dependence occurs within weeks to months of continued use.
3. withdrawal problems(abrubt cessation). recommended that
treatment periods be restricted to 34 months patient is tapered
off the drug to avoid withdrawal and supplementation with other
agents.
4. Abuse potential is low patients usually do not continue to
escalate their doses because tolerance of the anxiolytic action is not
prominentavoid in patients with a history of substance abuse or
risk factors for substance abuse
II. .Antidepressants:
SSRIs.
Venlafaxine approved for the treatment of generalized anxiety
and social anxiety disorders.
Duloxetine approved for generalized anxiety disorder. Some
initial symptoms may be improved within days, but the full
benefit oftreatment may take weeks, as for depression
treatment.
Tricyclic antidepressants have preventive efficacy for panic
disorder and anxiolytic activity.
Important note: About 25% of these patients experience a
hyperstimulatory response to antidepressants confused with a
worsening of the anxiety symptoms esp when therapy is first
begunUsing low doses at first
Antidepressants can also be helpful for anxiety that accompanies
depression.
III .Buspirone: Anxiolytic properties but controversy on its real value
in treating generalized anxiety disorder. It has little efficacy for panic
disorder.
Disadv:has long onset of action (weeks) the anxiety must be
covered with another agent( short-term benzodiazepines as a bridge
until buspirone takes effect)
IV .Miscellaneous agents
a. -Blockers block the peripheral symptoms of panic disorder or
performance anxiety.
b. MAOIs can be effective for the treatment of panic disorder when
the patient also has atypical depression.
Disadv: serious adverse effects.
c. Antihistamines with sedating properties (e.g., hydroxyzine) can
help reduce anxiety try them in patients with substance abuse
issues.
d. Barbiturates are seldom used. They are often less effective and
can be lethal if taken in overdose.
e. Antipsychotics not very helpful for anxiety, so use them only if
psychosis is also present.
Recommended Therapy for Specific Anxiety Disorders
1 .Generalized anxiety disorder
a. Benzodiazepines:
This class of drugs is rapidly effective; if possible, try to
discontinue in 34 months.
Long-term therapy is common but not recommended. We
usually do not see dose escalation unless the patient has
substance abuse issues.
Benzodiazepines can be taken in combination with either
antidepressants or buspirone as a bridge until these drugs start to
take effect.
b. Antidepressants: These take a little longer to work, but their use
avoids some of the long-term complications of benzodiazepines. They
are good long-term options, and many consider them firstline
agents.
c. Buspirone: Good when benzodiazepines should be avoided (e.g., in
patients with a history of substance abuse); takes 24 weeks to be
effective
d. Cognitive-behavioral therapy or another type of psychotherapy
should generally be included with pharmacotherapy.
2. Panic disorder
a. Benzodiazepines: High-potency agents; effective; rapid onset
b. Antidepressants: Take a little longer to work but are considered
first-line agents
c. Buspirone: Not effective.
d. Cognitive-behavioral therapy and other psychotherapies are
effective.
3. Obsessive-compulsive disorder
a. Serotonergic agents are effectiveSSRIs and clomipramine are
effective.
b. Cognitive-behaviorial therapy may be effective, but it is secondary
to pharmacotherapy.
c. SSRIs: alone often fail to control obsessive-compulsive disorder
completely. Not many other drugs help.
d.atypical antipsychotics show some success. In general, high doses
need to be used.
4. Posttraumatic stress disorder
a. Sertraline and paroxetine are considered first-line agents.
b. Treat specific symptoms (e.g., intermittent explosive behavior
with -blockers or mood stabilizers)
c. Valproic acid has been quite effective as well for reducing
aggression and anger; ECT has also been used.
5. Specific phobias
a. Not treated with medications
b. Systematic desensitization and other behavioral approaches often
effective
V. INSOMNIA
Normal Sleep Patterns and Neurochemistry/Physiology of Sleep
Sleep difficulties are common, with up to 35% of the
population affected. Of interest, 4%5% of the population may
experience hypersomnia.
Diagnosis: People with sleep problems usually experience one or
more of the following: insomnia, daytime sleepiness, or abnormal
sleep behaviors.
NB:. The sleep-wake cycle in humans usually lasts 25 hours, which
means that with the 24-hour day-night cycle of the earths rotation,
there must be some internal clock resetting. This resetting is
accomplished by cues such as clocks and daylight, which tell the time
of day.
Stages of sleep:

Passing from wakefulness to stage 4 non-REM sleep takes
about 45 minutes in young adults.
Rapid eye movement usually occurs within 90 minutes of
falling asleep; at first, REM lasts 57 minutes, but it gets
progressively longer through the night.
The sleep cycle (non- REM stages 14 and REM), which lasts
about 70120 minutes, is repeated four to six times a night.
The typical young adult spends about 75% of his or her time in
non-REM.
NB:Sleep patterns change with age. Elderly patients experience less
delta sleep, REM sleep, and total sleep time. They have more
nocturnal awakenings and total time awake at night. The incidence of
sleep pathology may be as high as 40%.


Brain regulation of sleep:
The neural networks regulating sleep-wake cycles are located
in the brainstem, basal forebrain, and hypothalamus, with
projections to the cortex and thalamus.
The reticular activating system maintains wakefulness, and
when activity here declines, sleep occurs.
Neuronal systems in the raphe nuclei, solitary tract, ventricular
thalamus, anterior hypothalamus, and basal forebrain promote
sleep.
Neurotransmitters of the sleep-wake cycle:
Norepinephrine, acetylcholine, histamine, and neuropeptides
operate in the hypothalamus during wakefulness.
serotonin (5HT):As the reticular activating system slows down,
neurotransmission in the raphe nuclei reduces sensory input and
inhibits motor activity.
NB: Norepinephrine is involved in dreaming, whereas serotonin is
active during non-dreaming sleep.
NB2: A lot of brain activity occurs during sleep; simultaneous
electroencephalograms, electro-oculograms, and electromyograms
characterize sleep stages. These are used to measure sleep latency
(time to sleep onset), number of awakenings, number of stage shifts
during the night, and latency to rapid eye movement (REM). These
recordings are termed polysomnography.

B. Sleep Disorders
Based on the DSM-IV:
a. Primary disorders
i. Dyssomnias: Primary insomnia; primary hypersomnia; narcolepsy
breathingrelated sleep disorder; circadian rhythm sleep disorder;
delayed sleepphase disorder; jet lag; dyssomnias not otherwise
specified
ii. Parasomnias: Nightmare disorder; sleep terror disorder;
sleepwalking disorder; parasomnias not otherwise specified
b. Sleep disorders related to another mental disorder: Insomnia
related to another mental disorder; hypersomnia related to another
mental disorder
c. Other sleep disorders: Sleep disorder caused by a general medical
condition; substance-induced sleep disorder
Insomnia
Def: an inability to initiate or maintain sleep, and it can be associated
with problems during the daytime.
Classification of insomnia:

Transient insomnia is most often associated with acute stressors. It
resolves once the acute stressors are removed. Pharmacotherapy
may be used for a few days until the situation resolves.
Short-term insomnia is also most often associated with an acute
stressor, but it is ongoing. Here, it is important to initiate good sleep
hygiene and avoid stimulants such as caffeine. Pharmacotherapy
may be indicated, especially if on an intermittent basis (e.g., skip it
after 2 or 3 good nights of sleep). Therapy for 710 days is usually
sufficient.
Chronic insomnia Evaluate for an underlying medical or psychiatric
cause If a cause is not present, then a common type of chronic
insomnia ( chronic psychophysiological insomnia), behavioral
problem.
The person has usually developed poor sleep hygiene, and the
bedroom is associated with an alerting response.--> Behavioral
therapy is important, but pharmacotherapy can be useful in
short courses and intermittently.
Ramelteon, eszopiclone, and zolpidem controlled release
useful in chronic condition.
Evaluation of insomnia :
Assessment of medical and psychiatric status: thyroid disease and
therapy with medications that can interfere with sleep. Several
psychiatric conditions can interfere with sleep, including affective and
anxiety disorders.
patients instruction about good sleep hygiene:
i. Maintain regular bedtimes and awakenings.
ii. Do not go to bed unless you are sleepy.
iii. Sleep long enough to avoid feeling tired, but no more.
iv. Optimize the bedroom conditions (e.g., light, temperature, noise).
v. Develop a bedtime ritual that allows you to unwind.
vi. If you cannot go to sleep, or if you awaken and cannot go back to
sleep, do not stay in bed more than 1520 minutes; get up and do
something else until you are sleepy.
vii. Do not go to bed hungry, but do not stuff yourself before bed; try
a small snack.
viii. Avoid activities in the bedroom except for sleeping and sex.
ix. Do not lie there and watch the clock; get one without a luminous
dial.
x. Avoid naps during the day.
xi. Avoid stimulants such as caffeine and nicotine throughout the day.
xii. Avoid alcohol because it can lead to fragmented sleep.
xiii. Exercise regularly during the day, but not close to bedtime.
Pharmacotherapy of Insomnia
Indicated for all forms of insomnia as long as it is part of an
overall plan to deal with the causes and is used for well-
defined times.
It should only be considered adjunctive therapy for short-term
or chronic insomnia.
Agents that can depress respiration should be avoided in
patients with respiratory disorders, a history of substance
abuse, or obstructive sleep apnea. Ramelteon should be
avoided with severe sleep apnea.
There are several classes of sedative-hypnotics: barbiturates,
which are no longer indicated; nonbarbiturates (e.g., chloral
hydrate), which have only limited indications; benzodiazepines;
and the non-benzodiazepines zolpidem, zaleplon, and
eszopiclone. Ramelteon is a melatonin 1 and 2 receptor
agonist.
Benzodiazepines:
safe, effective, and well tolerated by most patients.
five are primarily used as sedative-hypnotics because they are
rapidly absorbed and produce central nervous system actions more
quickly than most anxiety agents.
Classification:
. According to their half-life short acting (half-life less than 6 hours),
intermediate acting (half-life 624 hours), and long acting (half-life
more than 24 hours).
E.g: someone with problems initiating sleep would most likely benefit
from an agent with a quick onset but short duration of action.
Someone with problems maintaining sleep in the middle of the night
might do better on a drug with a longer half-life.


Adverse effects:
a. Tolerance: particularly when the drugs are used consistently for
long periods not indicated for chronic use evidence is emerging
that they may be effective for longer periods than originally thought.
(Most are effective for 24 weeks or longer)
An intermittent pattern of use reduce the development of
tolerance.
Most people without substance abuse histories do not escalate
their doses.
b. Residual daytime sedation: common complaint especially with
agents having a long half-life. Dose is also an important factor; always
use the lowest effective dose.
c. Rebound insomnia: when the drug is discontinued abruptly
Insomnia is usuallyworse than baseline and usually lasts for 12
daystapering the drug .
Most common after the use of short- and intermediate-acting
agents.
d. Anterograde amnesia: All benzodiazepines appear to impair the
acquisition and encoding of new information. They may also impair
memory storage and recall. Dosage may be important.
Cautions in elderly patients because they can cause memory
problems, increase the risk of falls, and accumulate (agents with a
long half-life). Try to avoid use in this population.
e. Idiosyncratic reactions can occur in elderly and pediatric
populations withbenzodiazepine use.
f. Withdrawal: Physical dependence will occur if these agents are
used long enough.
Symptoms of withdrawal include worsening insomnia, anxiety,
muscle twitches, photophobia, tinnitus,auditory and visual
hypersensitivity, and seizures. gradually tapering the drug
atdiscontinuation.
.Zolpidem (Ambien): non-benzodiazepine sedative-hypnotic
modulates the GABAA receptor complex.
Compared with benzodiazepines, zolpidem lacks
anticonvulsant action, muscle-relaxant properties, and
respiratory depressant effect; it also has a lower risk of
tolerance and withdrawal.
It should still be avoided in obstructive sleep apnea. It is a good
choice for patients in whom benzodiazepines should be
avoided.
The half-life of zolpidem is about 1.54.0 hours in healthy
adults longer in both renal and hepatic disease dose must
be lowered.
SE: headache, dizziness, daytime somnolence, and GI
complaints have been noted.
Ambien controlled release releases some of the drug quickly later
releases the second portion of the dose to help prevent early
awakening. Ambien controlled release can be used for longer-term
therapy if needed.
Zaleplon (Sonata): This is a non-benzodiazepine with a similar
pharmacology and a very short half-life.
For patients with sleep maintenance problems Not good
choice might not last as long.
SE: However, it has a shorter halflife )about 1 hour) and may
cause fewer problems in the morning, especially if given late.
Eszopiclone (Lunesta): This non-benzodiazepine is a GABAA
agonist. Its half-life is 6 hours morning effects could result if
it is taken late in the night.
This drug can be used for chronic insomnia.
Cautions: Patients should be warned about the potential risk of
engaging in abnormal activities while asleep when taking sedative-
hypnotics. Such behaviors may include driving, eating, having sex, or
talking on the phone while asleep (with amnesia for the event). (2)
anaphylaxis and decreased respiratory drive.
Ramelteon (Rozerem): Melatonin agonist (no activity at GABA or
benzodiazepine receptor).
Duration is 25 hours.
No evidence of dependence or tolerance can be used long
term good choice for chronic insomnia.
Over-the-counter medications: often antihistamines that are both
sedating andanticholinergic. They are possibly effective, but not as
effective as benzodiazepines.
Their regular use is not recommended. do not maintain efficacy
beyond a few days
higher incidence of daytime sedation than short- or intermediate-
acting benzodiazepines.
Diphenhydramine has been a popular agent when benzodiazepines are
contraindicated.
Cautions:
Elderly patients because an anticholinergic action can worsen
dementia or other medical conditions.
Should not be administered with the cholinesterase inhibitors
used for Alzheimer disease.
Other non-benzodiazepines:
Antidepressants such as TCAs and trazodone may be used as
sedative-hypnotics. These can be effective, and often, the dose
required is lower than that used for depression. However, efficacy
has not been fully established through clinical trials.
Trazodone used for managing insomnia caused by SSRI
antidepressants+Itself as a sleep agent because the potential for
dependence is low.(Not for long term use due to many SE)
VI. SUBSTANCE ABUSEALCOHOL
Acute Withdrawal
symptoms after alcohol discontinuation Depend on the level of
alcohol abuse and a persons characteristics.

Delirium tremens life threatening, should be considered a potential
medical emergency and treated promptly.
Seizures difficult to control. Status epilepticus can develop; thus, it is
important to ensure that these patients have intravenous access.
Benzodiazepines are first line for seizure prevention in alcohol
withdrawal compared with other anticonvulsants.
Treatment of Acute Alcohol Withdrawal
Individualized therapy according to symptoms severity + accurate
history regarding amount, duration, and past withdrawal symptoms
including seizures and delirium tremens should guide treatment.
complications may arise, treatment should take place in an inpatient
setting.
The principle of cross-tolerance is used to advantage in the
prevention and treatment of withdrawal symptoms. Benzodiazepines
can eliminate many manifestations of withdrawal and are much
easier to control with respect to dosing.
a. Intermittent dosing: patients are assessed for the severity of
withdrawal symptoms the benzodiazepine dose is adjusted to that
level the most prevalent way of treating these patients.
b. Scheduled dosing: Begin a scheduled dose of benzodiazepine on
admission, give it regularly, and then taper it down for 34 days until
symptoms have abated.
c. Loading-dose (front loaded) protocol: uses a loading-dose strategy
for diazepam given in a dose of 1020 mg every 12 hours until the
symptoms of withdrawal are alleviated. Most patients will need 2-3
doses(especially those with a history of seizures during withdrawal)
three doses should be used.
NB:The half-life of diazepam is long, and most patients will not need
subsequent doses in this protocol once symptoms are relieved(
patients should be monitored closely).
Chlordiazepoxide The classic member given either orally or
parenterally no advantages over the other agents; its long half-
life may cause unnecessary sedation.
patients with a high risk of withdrawal seizures or delirium
tremenslong-acting benzodiazepine may be preferable.
If a shorter-acting agent is used, a round-the-clock schedule
would be ideal for high-risk patients.
Lorazepam is also safe to administer in patients with liver
disease.

Nutritional considerations
a. Thiamine: This should be given to all patients to prevent Wernicke-
Korsakoff syndrome100 mg intramuscularly on admission and then
orally for 3 days; always give the first dose before glucose because it
is a cofactor for the metabolism of glucose.
b. Magnesium: Assess by serum chemistry; if low, give intravenous
supplement.
c. Electrolytes: Assess by serum chemistry and add to intravenous
solutions as indicated (e.g., potassium).
d. Vitamins: These patients are usually undernourished; a good
multivitamin may be indicated (folate and vitamin B12 should be
monitored).
Fluid therapy: The patient may initially be overhydrated, but usually,
fluid deficit will follow; replace fluids, usually with intravenous 5%
dextrose solution with half-normal saline plus other electrolytes (e.g.,
potassium, phosphate).
Hallucinations: Benzodiazepine will usually manage hallucinations
effectivelyif not, give haloperidol; however, be cautious because
haloperidol can lower the seizure threshold.
Seizures: Benzodiazepine will usually prevent seizures. Higher doses
(and/or increased frequency) of benzodiazepines can be used if the
patient has a history of seizures.
If a seizure occurs during withdrawal increasing the dose of
benzodiazepine and slowing the taper
other antiepileptics may be used to treat status epilepticus, but
their efficacy varies.
8. Other agents
a. -Blockers: These agents help with vital signs and blood pressure.
b. -Agonists (e.g., clonidine): These agents may help with some of
the withdrawal symptoms.
C. Chronic Therapy
1. Disulfiram: This drug blocks acetaldehyde dehydrogenase, and if
alcohol is used with it, the person will develop symptoms that include
nausea/vomiting, flushing, and headache, among others. Adherence
is critical, and disulfiram is usually reserved for patients with
considerable motivation for adherence.
2. Naltrexone: This drug can also be used chronically and has been
shown to reduce cravings.
should be combined with cognitive-behavioral therapy.
Liver toxicity is associated with this drug.
Extended-release injectable suspension (Vivitrol) is available in an
intramuscular formulation and is approved for the treatment of
alcohol dependence in patients who are able to abstain from alcohol
in an outpatient setting before treatment initiation.
2. Acamprosate (Campral): New drug is a structural analog of GABA.
It, too, reduces cravings.
It is not metabolized by the liver; however, it must be taken three
times/day.