Integrated Treatment of Schizophrenia: Il Trattamento Integrato Della Schizofrenia

Dimensional psychopharmacology
Integrated treatment of schizophrenia

Il trattamento integrato della schizofrenia
A.C. Altamura1, A. Fagiolini2, S. Galderisi3, P. Rocca4, A. Rossi5
1
Department of Psychiatry, University of Milan; 2 University of Siena, Department of Molecular Medicine, Department of Mental Health;
3
Department of Psychiatry, Second University of Naples SUN; 4 Department of Neuroscience, University of Turin; 5 Department
of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Italy
Summary It has been made a considerable effort to improve adherence

Psychosocial therapies play an important role in the treatment to antipsychotic treatment through the development of drugs
of schizophrenia. These therapies are aimed at improving the with better tolerability, in formulations that enable long-term
functioning of the patient in the community, which in turn can administration of the drug, including injectable long-acting (de-
lead to clinical improvement, such as reduction in the number pot) antipsychotics. In recent years the development of these
of relapses or hospitalizations. Substantial evidence supports the
formulations of atypical antipsychotics and the promising results
use of many psychosocial therapies in schizophrenia, including
cognitive behavioral therapy, assertive community treatment, obtained in clinical trials are changing the attitude toward these
cognitive remediation and functional skills training. drugs, traditionally reserved for patients with repeated non-ad-
The customization of pharmacological therapy in schizophrenia, herence to treatment.
besides the experience of the clinician and individual prefer-
ences of the patient, should be based on three sets of objective Key words
data: 1) clinical predictors of response to therapy; 2) predict-
able side effects of therapy; 3) pharmacogenetic and pharma- Pharmacological treatment • Rehabilitative and psychosocial psycho-
cogenomic data. therapy
Pharmacological treatment, rehabilitative Thus, the psychiatrist should be part of a multidisciplinary

team, composed of mental health professionals and other
and psychosocial psychotherapy
medical specialists, as well as providers of social services
S. Galderisi and other relevant entities (e.g. authorities who organise
housing and employment).
Introduction
Schizophrenia is caused by complex interactions between Treatment with antipsychotics
biological, genetic and environmental factors; as a conse- Antipsychotics are a fundamental element of treatment of
quence, patients affected by the disorder should receive schizophrenia 2. Undoubtedly, they are very effective in
integrated treatments that include drugs and psychosocial reducing the positive symptoms of schizophrenia. How-
therapy, care of physical health and treatment of comor- ever, at present, the available antipsychotics have signifi-
bidities. In general, drugs are administered in the initial cant limitations (Table I); in particular, negative symptoms
phases of schizophrenia when symptoms lead to an indi- and cognitive alterations are not treated adequately, and
vidual to consult psychiatric services. Psychosocial thera- many patients continue to present persistent psychotic
pies are frequently not initiated until the appearance of symptoms. In addition, the lack of insight that accom-
uncontrolled symptoms. This model could change, how- panies schizophrenia is a partially unsolved problem.
ever, once early diagnosis and timely therapeutic inter- Clinical studies have consistently demonstrated that an-
vention become more common and non-pharmacological tipsychotics reduce positive symptoms such as delirium
treatments can be initiated at an earlier stage. An integrat- and hallucinations 3 4. In this regard, large studies have
ed and multifaceted approach involving drugs, psycho- demonstrated that second-generation agents are at least as
social interventions and attention to environmental cir- efficacious (if not more so according to some studies) than
cumstances can improve the outcomes of schizophrenia1. first-generation antipsychotics, and that they are generally
Corrispondenza
A. Altamura • E-mail: [email protected]; A. Fagiolini • E-mail: [email protected]; S. Galderisi • E-mail: silvana.galderisi@gmail.
com; P. Rocca • E-mail: [email protected]; A. Rossi • E-mail: [email protected]
168 Journal of Psychopathology 2015;21:168-193

better tolerated with a reduced propensity to induce ad- al population 13. Suicidal behaviour is present in about
verse effects such as motor symptoms; accordingly, they 50% of affected individuals and about 5-10% of persons
are associated with better compliance 3 5. The safety pro- with schizophrenia commit suicide. Clinical studies with
files of older and newer agents, however, are significantly some antipsychotics have shown that they are associated
different 5. with a reduction in suicidal behaviour 14.
Antipsychotics have been shown to be effective in the Limitations of antipsychotics
treatment of acute psychotic episodes 6. About 85% of The negative symptoms of schizophrenia, such as apa-
previously untreated patients show improvement of thy, anhedonia and decreased emotional expression, can
symptoms and 60% remain in remission at 3 years7. Ef- be present at the onset of disease and may represent the
fective, timely treatment of psychoses in the initial phases predominating symptoms; in fact, in around 70% of cases
can avoid a long duration of untreated psychosis, which these symptoms develop before positive symptoms 3. In
is associated with poorer clinical and social outcomes 8 9. reality, there is evidence to support the existence of a
Maintenance therapy reduces the risk of relapse in pa- form of disease (deficit schizophrenia) that identifies a
tients with schizophrenia. An analysis of 65 clinical stud- subgroup of patients characterised by the presence of
ies involving more than 6000 patients with schizophrenia primary and persistent negative symptoms 15. The avail-
demonstrated that maintenance treatment reduces the able antipsychotics have a limited effect on negative
incidence of relapse and hospitalisation by around 60% symptoms and are ineffective on primary and persistent
(Fig. 1) 10. It is important to highlight that this analysis symptoms 3. This limitation is an important problem since
also showed that the number needed to treat (NNT) of negative symptoms are associated with compromised
pharmacological therapy is related to adequate psycho- employment and social functioning, and are thus a sig-
social therapy: under these conditions, in fact, treatment nificant obstacle in maintaining an independent life 16.
of only 3 patients for 7-12 months can prevent another Almost all patients with schizophrenia have deficits in
relapse and treatment of 5 patients can prevent another cognitive function, which affects domains such as ver-
hospitalisation 10. bal fluency, memory, attention, velocity of elaboration,
In some patients, relapse can delay or halt progression of ability to assign priorities and make decisions 3. Such
disease 11. Moreover, by preventing relapse and improv- deficits present early in the course of disease, in general
ing insight, antipsychotics can assure a period of stabil- years before the appearance of overt psychosis, and are
ity and facilitate the introduction of additional treatments strong predictors of compromised social functioning and
such as psychosocial therapy 12. There is evidence that unfavourable outcomes. Unfortunately, currently-avail-
the greater the improvement of symptoms after the start able antipsychotics have limited impact on the cognitive
of pharmacotherapy, the greater the probability of a good symptoms of schizophrenia: any improvements observed
response to psychosocial therapy 12. appear to be correlated with a reduction in other symp-
Behavioural symptoms such as hostility and aggression toms rather than to direct effects on cognitive ability 17 18.
are common in schizophrenia, and there is evidence that Antipsychotics are associated with several collateral ef-
these symptoms are susceptible to antipsychotic drugs 13. fects that can be severe and limit adherence to therapy,
In general, good adherence to therapy seems to be as- thus decreasing the possibility of recovery (Table II) 3.
sociated with low levels of aggression, and persons with Individual antipsychotics differ in their safety profile,
schizophrenia who adhere to therapy and are clinically but some adverse effects, such as motor symptoms and
stable do not seem to be more violent than the gener- metabolic hormonal disorders, are common to all these
Table I.
Potential benefits and limitations of current antipsychotic medication (from Fleischhacker et al., 2014, modified) 1. Possibili
benefici e limiti degli attuali farmaci antipsicotici (da Fleischhacker et al., 2014, mod.) 1.
Benefits Limitations
Reduction of positive symptoms Limited efficacy against negative symptoms
Treatment of acute episodes Inadequate treatment of cognitive impairment
Reduced risk of relapse Troubling side effects or tolerability issues
Provision of stability and a platform for other treatments Low acceptability to some patients
Reduction of aggression and hostility • Poor adherence
• Negative perceptions
Reduced suicidal behaviour
169
A.C. Altamura et al.
non-adherent to oral therapy 19, even if this percentage

is higher in long-term studies. The main reasons for low
70
64 adherence include:
Untreated • lack of information about the disease and its treat-
60
Treated ment;
Proportions of patients (%)
50 • lack of improvement of psychotic symptoms;

• adverse effects (that resolve if the patient interrupts
40 therapy);
• lack of knowledge about the need for treatment;
30 27 26 • economic difficulties (especially in countries in eco-
20
nomic difficulty);
• complexity of treatment schemes;
10
10 • fear of discrimination;
• poor physician-patient relationship;
0 • lack of support by caregivers.
Relapse Hospitalisation
The lack of adherence to therapy is commonly associated
with relapse, which often leads to hospitalisation; how-
FigurE 1. ever, the association between adherence and hospitalisa-
Long-term treatment of schizophrenia (maintenance) tion can also depend on the fact that lack of adherence
significantly reduces the number of relapses (7-12 months) and may represent a symptom of progression of disease 20.
the number of hospitalizations in patients with schizophrenia, The frequency of hospitalisation (often used as an indica-
compared with placebo (data from a combined analysis of tor of severe relapse) is up to 400% higher in non-adher-
65 clinical trials) (from Leucht et al., 2012, modified) 10. La ent patients than those who are adherent to therapy 21.
terapia antipsicotica a lungo termine (di mantenimento) riduce
Moreover, non-adherent individuals have a greater prob-
in maniera significativa il numero di recidive (a 7-12 mesi) e
il numero di ricoveri nei pazienti con schizofrenia, rispetto ability of low overall function in the long term and to be
al placebo (dati derivanti da un’analisi combinata di 65 trial
clinici) (da Leucht et al., 2012, mod.) 10.
Table II.
Potential side effects of current antipsychotic medication
drugs. In general, typical antipsychotics tend to have (from Fleischhacker et al., 2014, modified) 1. Possibili effetti
more motor effects, while several atypical antipsychotics collaterali degli attuali farmaci antipsicotici (da Fleischhacker
can cause metabolic adverse effects; all first-generation et al., 2014, mod.) 1.
antipsychotics and most second-generation antipsychot-
• Extrapyramidal symptoms
ics can cause hyperprolactinaemia, with the exception of –– Slow, stiff movement and tremor (parkinsonism)
aripiprazole, clozapine and quetiapine. Motor symptoms –– Abnormal muscle tone/muscle spasms (dystonia)
influence movement and muscular tone and can lead to –– Involuntary movements (tardive dyskinesia)
Parkinsonism (tremor and muscular rigidity) and muscle –– Subjective experience of restlessness and restless move-
spasms (dystonia) as well as subjective and objective rest- ments (akathisia)
lessness (akathisia). These symptoms are known collec- • Weight gain
tively as acute extrapyramidal symptoms (EPS). Another
• Metabolic disturbances
EPS, which usually appears late in the course of treatment
–– Changes in blood glucose levels
together with aging of the patient, is tardive dyskinesia, –– Increases in cholesterol and triglycerides
a symptom characterised by involuntary and repetitive
• Sedation
movements of the limbs, trunk and more characteristical-
ly of the libs, tongue and jaw. Metabolic disorders include • A feeling of being ill-at-ease (dysphoria)
weight gain and changes in blood glucose, cholesterol • Hormonal changes
and other lipids. These disorders can negatively influence • Sexual dysfunction
the physical health of patients with schizophrenia. Other
• Changes in the electrical activity of the heart (rare)
hormonal disorders, and in particular an increase in the
levels of prolactin, can give rise to secondary problems • Neuroleptic malignant syndrome (a rare but life-threaten-
ing neurological disorder)
such as sexual dysfunction.
Adherence to antipsychotic therapy is often low in per- • Agranulocytosis (very low levels of white blood cells, also
sons with schizophrenia 5: about 50% of patients are life-threatening but rare)
170
more violent and attempt suicide more frequently than Assertive community treatment
patients who are adherent to therapy. Assertive community treatment (ACT) is a model that
Adherence to antipsychotic therapy can be improved was developed to improve the rate of relapse and hos-
through better understanding of the individual motiva- pitalisation following the transition from institutionalisa-
tions for the lack of adherence and involving the patient tion to territorial care in the USA starting in the 1980s 25.
in treatment decisions. One possible obstacle to adher- This approach, aimed at a subgroup of patients who are
ence is the common practice of using polytherapy to con- strong users of services, involves a multidisciplinary team
trol symptoms, which renders it difficult for patients to re- working in the community to provide a range of services
member when to take various medications. Polytherapy, comprising management of pharmacological therapy,
whenever possible, should be avoided. In addition, the practical support (e.g. housing) and rehabilitation. ACT
use of long-lasting injectable formulations (depot) of an- is characterised by a high frequency of outpatient visits
tipsychotics may be associated with better adherence 22. and a low number of patients (usually about 10) who
An individualised approach to therapy should be encour- are followed by each member of the team: these two
aged, which should also include patient preferences 1. characteristics obviously require considerable resources,
Drugs with tolerability and safety profiles that are ade- even if it has been demonstrated that, for treatment of
quate to the needs of the patient should be chosen (e.g., schizophrenia as for other psychological therapies, an in-
avoiding drugs that lead to weight gain if this represents crease in the time spent with the patient can contribute to
a problem). Weight gain can be a significant problem in achieving positive results 24 25. Studies in several countries
younger patients. About 25% of patients with a new di- have demonstrated that ACT is associated with a lower
agnosis of schizophrenia are less than 18 years of age incidence of homelessness and hospitalisation compared
and can be particularly sensitive to side effects such as with standard care in patients who are frequent users of
weight gain or menstrual cycle disorders associated with services 24-26. One analysis revealed that, on average,
drug-induced hormonal changes. Careful and frequent there is a reduction in homelessness by 37% in patients
monitoring of adverse effects should be carried out in all undergoing ACT compared with standard care 26. Even
patients undergoing long-term therapy. if ACT can help individuals with schizophrenia to live
Antipsychotics are effective in reducing psychotic symp- a stable life in the community, several studies have sug-
toms, but many patients show only partial response to gested that it has a relatively limited impact on other
treatment 3. Even when patients obtain remission, few outcomes such as social functioning or employment. Re-
are completely free of symptoms. Moreover, up to one- cently, the OPUS study 27, carried out on patients with
third of patients affected by schizophrenia show a poor a first episode of schizophrenia, showed that ACT was
response to antipsychotics, and some develop resistance superior to standard therapy in reducing both positive
to treatment. Treatment resistance generally occurs with and negative symptoms and substance abuse, increasing
disease progression 23, but in about 10% of cases it is overall patient satisfaction and adherence to therapy and
already evident after the first episode 19. in reducing the number of hospitalisations.
Cognitive-behavioural therapy
Psychosocial therapies
Psychotic symptoms can persist despite antipsychotic
In addition to pharmacological therapy, psychosocial medications, which constitute a large obstacle to social
therapy also plays an important role in treatment of recovery. CBT (a talking therapy that helps people man-
schizophrenia 1 24 25. These therapies have the aim of im- age their disease by changing their way of thinking and
proving the functioning of the patient in the community, listening) directed towards psychotic symptoms aims to
which can also lead to clinical improvement, such as a reduce their severity and consequent distress 24 25. Many
reduction in the number of relapses or hospitalisations. studies have demonstrated that this approach improves
The use of psychosocial therapies is supported by sub- social functioning, reduces positive and negative symp-
stantial evidence; these include cognitive behavioural toms and decreases mood disorders vs a control group.
therapy (CBT) for psychosis, in addition to cognitive re- Other studies, however, have not demonstrated such im-
mediation and functional skills training; other approach- provements, and the effects of CBT on outcomes such as
es also appear promising (Tables III, IV) 1 24 25. Schizophre- hospitalisation, depression, suicidal tendency and insight
nia associated disabilities often involve several areas, and have not been clearly established 28. A recent systematic
psychosocial therapies can be combined to confront a review concluded that CBT does not offer a clear advan-
range of problems. For example, social skills training can tage over other psychosocial therapies such as family
be used as part of an integrated program that includes therapy and psychoeducation 29. Evidence supporting the
family psychoeducation, cognitive remediation and CBT. use of CBT is largely shown by studies in which partici-
171
table III.
Many psychosocial interventions have been shown to improve outcomes in schizophrenia (evidence-based approaches), and
others are being developed and evaluated (promising approaches) (from Fleischhacker et al., 2014, modified) 1. Molti interventi
psicosociali hanno dimostrato di migliorare l’outcome nella schizofrenia (approcci evidence-based) e altri sono in fase di sviluppo
e di valutazione (approcci promettenti) (da Fleischhacker et al., 2014, mod.) 1.
Evidence-based approaches Promising approaches

• Assertive community treatment • Cognitive adaptive therapy
• Cognitive behavioural therapy for psychosis • Healthy lifestyle intervention
• Cognitive remediation • Interventions targeting older individuals
• Family therapy/psychoeducation • Prodromal stage intervention
• Peer support and self-help strategies • Social cognition training
• Social skills training • Social rehabilitation (Clubhouse Model)
• Supported employment
• Integrated treatment for coexisting substance abuse disorder
table IV.
Potential benefits of psychosocial therapies (from Fleischhacker et al., 2014, modified) 1. Possibili benefici delle terapie psicosociali
(da Fleischhacker et al., 2014, mod.) 1.
Intervention Potential benefits

• Assertive community treatment • Reduction in rates of homelessness and length of hospital stays
• Cognitive behavioural therapy for psychosis • Decreases in both positive and negative symptoms and mood
disturbances, and improved social functioning
• First episode intervention for psychosis • Improvements in quality of life, social functioning and adherence
• Cognitive remediation • Improvements in cognition and psychosocial functioning
• Family psychoeducation • Some improvement in social functioning and family coping and
empowerment
• Peer support and illness self-management training • Enhancement of empowerment and ability to cope with the illness
• Social skills training • Improvements in social functioning
• Supported employment • Increases in employment rates, hours worked and wages earned.
Gains in self-esteem and quality of life
• Integrated treatment for coexisting substance • Reductions in substance use and arrests; improved functioning
abuse disorder
pants received at least 16 sessions 6: CBT requires special- ity of studies have revealed that this approach is effec-
ist training and experience, and thus cost is an important tive in improving cognitive function, while its effects on
consideration. An analysis by the National Institute for psychosocial functioning have been quite variable 24 25.
Health and Care Excellence (NICE), however, concluded Models for cognitive remediation differ greatly and the
that CBT likely has a good cost-efficacy ratio, since the number of reliable studies in this area is rather limited.
costs are compensated by a decrease in hospitalisation 6. It has been suggested that cognitive remediation aug-
ments the effects of other types of psychotherapy and
Cognitive remediation improves the capacity to learn new abilities. Moreover,
Cognitive remediation programs usually utilise exercises there is very limited evidence that its use for 2 years is
aimed at improving aspects related to cognitive function, associated with a reduction in the loss of cerebral grey
often combined with teaching strategies to improve the matter correlated with schizophrenia 30 and an increase
results of such exercises; these can also include differ- in the number of connections between brain cells and
ent ways to limit cognitive deterioration 24 25. The major- functional networks 31. In a meta-analysis on over 2000
172
patients, 32 a long-lasting, mild-moderate effect of cogni- personnel guide a group of individuals with schizophre-
tive remediation was seen on cognitive function and on nia and their families who are given information about
overall functioning that did not depend on the methodol- the course of disease and treatment of psychotic disor-
ogy of the study (type of approach, duration, etc.). Cogni- ders. Participants also undergo problem-solving exercises
tive remediation was more effective when patients were that are designed to specifically help them to deal with
clinically stable, and greater significant differences were the difficulties associated with care of a person with a
seen on functioning when cognitive remediation was car- psychotic disorder 37. A multifamily approach can signifi-
ried out in combination with other forms of psychiatric cantly reduce the rates of relapse compared with mono-
rehabilitation 32. family psychoeducation, which already reduces the rates
of relapse vs treatment with no family psychoeducation
Family psychoeducation (Fig. 2) 38. Moreover, the addition of multifamily group
Many persons with schizophrenia live with their families, psychoeducation to therapy with antipsychotics doubles
and as such family intervention (also known as family the effects of pharmacological therapy alone 38.
psychoeducation in the USA) can play an important role Paradoxically, however, providing information can in-
in care 24 25. Education of patients and families about the crease self-stigma of persons with schizophrenia, induc-
nature of schizophrenia and the symptoms of the disease ing them to expect prejudice and discrimination. The
helps them to develop coping strategies, capitalise on potential impact of self-stigma is shown in the Interna-
their strengths and learn to take better care of oneself. Pa- tional Study of Discrimination and Stigma Outcomes, an
tients (and their families) treated with family intervention international study carried out in 27 countries in which
are better able to participate in shared decisional pro- 64% of participants referred that they no longer looked
cesses. Family psychoeducation offers a valuable oppor- for employment, training, or education, and almost 75%
tunity for persons with schizophrenia, their families and said they felt the need to hide their diagnosis because of
healthcare providers to exchange their personal experi- predictable discrimination 39. However, in the long-term,
ences about the disease and its treatment. It is important psychoeducation – supported by adequate antipsychotic
to highlight that family members can provide a continuity and psychosocial therapies – seems to be effective in
of care for persons with schizophrenia, even if the health- reducing the burden experienced by many people with
care operators involved in treatment change over time. A schizophrenia and their families 28.
psychoeducational approach aims to promote collabora-
tion between the family and healthcare providers. Stud- Mutual support and self-help strategies
ies have consistently shown that psychoeducational ap- Persons with schizophrenia and their caregivers have
proaches are effective in reducing the rates of relapse and noteworthy and accurate comprehension of the problems
hospitalisation and in improving social functioning 24 25.
There is also evidence that these benefits are long-lasting
(> 5 years) 33. Since according to other studies the effects
70 65
of family psychoeducation tend to subside after about 2
years due to an extinguishing effect, it has been suggested 60
2-years relapse rate (%)
that ‘recall sessions’ in a multifamily setting may be use- 50

ful in reducing the economic impact 34. An initial analysis 40
demonstrated that relapse and hospitalisations can be re- 30 27
duced by about 20% when family members are included 20 16
in treatment compared to traditional care 35. In another 10
study, the rate of relapse at 2 years was 40% in patients 0
in whom families received psychotherapeutic interven- No family Single-family Multi-family
psychoeducation psychoeducation psychoeducation
tion and 75% when families did not receive any interven-
tion 36. The greatest advantages of family psychoeduca-
tion seem to be present in persons with a first episode Figure 2.
of psychosis or recent onset of schizophrenia. Moreover, Family psychoeducation reduces schizophrenia relapse rates,
the benefits of psychoeducation also extended to fam- compared with treatment without family psychoeducation, and
ily members who referred reduced levels of stress, better multifamily group psychoeducation is particularly effective
(from Fiorillo et al., 2011, modified) 34. La psicoeducazione
family relationships and greater ability to cope with prob-
familiare riduce la percentuale di recidive di schizofrenia
lems and responsibilities 28. rispetto al trattamento senza psicoeducazione familiare, e la
Group multifamily psychoeducation is another useful in- psicoeducazione multifamiliare di gruppo è particolarmente
tervention based on the family. In this model, qualified efficace (da Fiorillo et al., 2011, mod.) 34.
173
associated with the disease. As a consequence, mutual petitive job according to most studies 28. The principal
support interventions can have an important role in the characteristics of such interventions are: focus on com-
management of schizophrenia; this type of approach has petitive employment; rapid search for work rather than a
been actively promoted in the USA and UK 40. Mutual lengthy work training program; integration of psychiatric
support groups, such as the National Alliance on Mental and employment services; emphasis on individual work
Illness (NAMI), the European Federation of Associations preferences; continuous support in the workplace.
of Families of People with Mental Illness (EUFAMI) and One of the most utilised supported employment models
the GAMIAN-Europe work together for affected individu- is Individual Placement and Support (IPS), according to
als and caregivers. These groups can provide support in which the only criterion for admission is the desire of the
a number of different areas 40. While peer-to-peer coun- person to have a competitive job. The IPS model can pro-
selling seems to be useful when included as part of rou- duce notable savings in both social and healthcare costs,
tine care, a self-help approach is generally more effective as well as potential benefits for the individual in terms of
in other contexts (e.g., alcohol abuse or weight control) fewer hospital admissions and increased rates of employ-
than in schizophrenia. However, in a recent report by the ment 49. Supported employment, however, has not been
Schizophrenia Commission in the UK, 48% of patients clearly demonstrated to improve long-term employment
with schizophrenia identified a self-help strategy as an and economic independence in patients with schizophre-
important part of individual care 41. There is also some nia. For this reason, it has been suggested that these strate-
evidence that self-help strategies can be useful in delay- gies be adequately integrated with interventions such as
ing hospital readmission, even if one study found no dif- CBT, cognitive remediation and social skills training 28.
ference in clinical or social outcomes between individu- Even if access to employment has a positive impact on
als who participated in self-help groups compared with mental health, the right type of employment must be
those who did not 42. considered: workplaces with low overall quality can
cause stress, which can lead to psychological prob-
Social skills training lems 47. This is an important point since employers often
In persons with schizophrenia, problems in psychoso- have low expectations of persons with schizophrenia,
cial functioning are related to disabilities in social skills and thus sometimes believe these individuals can only
that may be present before the onset of disease and per- carry out jobs requiring low skill sets or with limited
sist if they are not addressed 24 25. Social skills training responsibility, or only volunteer work 48. Retribution of
can improve social proficiency, daily life, community work can be useful for persons with schizophrenia, even
functioning and other aspects of social functioning. The if this carries the additional risk of interrupting routine
approach also has a small but significant effect on re- and consolidated habits.
lapse 43. The value of social skills training can be limited
in some way to cognitive dysfunction in persons with Limitations of psychosocial therapy
schizophrenia 43; however, its integration with cognitive Psychosocial therapy has some limitations that cannot
remediation programs (or strategies aimed at improving be appreciated if symptoms are not well controlled and
attention and cognitive capacity), seem to be useful in patients are not aware of their condition and the need to
improving the acquisition of social skills in patients with treat it. Involving the patient in the choice of treatment,
schizophrenia 44-46. for example, can be important in achieving a positive
outcome: individuals who are highly motivated generally
Supported employment respond better to cognitive remediation than those who
Schizophrenia can significantly reduce the ability of are less motivated 50. Moreover, some persons affected
a person to work: on average, only 10-20% of persons with schizophrenia, if not treated with antipsychotics,
affected with schizophrenia participate in the competi- can worsen when subjected to psychosocial interven-
tive workplace 24 25. Persons with severe mental disorders tions 51. The costs of some therapies, such as CBT, can be
such as schizophrenia are 6-7 times more likely to be prohibitive in countries in which adequate public health-
unemployed than those without such disorders 47. Data care resources are not available.
from the UK suggest that only 8% of persons with schizo- The design of studies aimed at investigating the efficacy
phrenia are employed, despite evidence that many would of psychosocial therapies is not always as robust as the
like to work 48. Supported employment approaches can methodology applied to clinical studies for authorisation
help persons with schizophrenia to obtain competitive of a new drug. Thus, precisely planned, randomised con-
employment, work longer and have higher salaries than trolled studies with adequate enrolment are needed in
persons without such support 26. At least 50% of individu- order to make strict recommendations regarding the use
als who receive supported employment obtain a com- of these treatments.
174
Individualisation of treatment second-generation antipsychotics (clozapine, olanzap-

ine, thioridazine, risperidone, quetiapine for weight gain
in schizophrenia
and metabolic effects; ziprasidone for increasing the QTc
A. Rossi interval) have caused significant concern (Tables VI-X).
In spite of the progress made in psychopharmacology,
Introduction many patients with schizophrenia interrupt or switch
antipsychotics for lack of efficacy and/or treatment-
In spite of significant progress in understanding the na- adverse events, and a large proportion of patients re-
ture of the disease, schizophrenia remains a challenging main symptomatic despite treatment. Individualisation
condition to treat. Schizophrenia is characterised by high of pharmacological treatment in schizophrenia, in ad-
morbidity and mortality: available treatments are inad- dition to clinical experience and patient preference,
equate, with variable efficacy, and are associated with should be based on three types of objective data: 1)
several adverse effects. In spite of these obstacles, how- clinical factors predictive of response to therapy; 2) pre-
ever, the availability of a wide range of individualised dictable adverse effects of therapy; 3) pharmacogenetic
treatments, rehabilitative services and social support can and pharmacogenomic data.
effectively promote recovery of persons with schizophre-
nia 52 (Fig. 3). In reality, even if current antipsychotic treat-
ments are not completely sufficient, they can nonetheless Clinico-demographic variables and prevalent
significantly reduce the burden of disease and improve clinical dimension as predictive factors
daily life of patients. Towards this end, critical evalua- of response to therapy
tion of the considerable amount of available information The factors that influence variability of response to ther-
on antipsychotics and their individualised use is essen- apy with antipsychotics have not been clarified, thus
tial, and further efforts are needed to answer clinically rendering it difficult to develop effective treatment strat-
important questions 53-57. In clinical practice, decisions egies for individual patients. The identification of clini-
about the best antipsychotic with which to initiate treat- cal factors associated with outcomes in the treatment
ment – or switch to another following treatment failure – of schizophrenia would be of significant advantage in
is essentially an empirical process, since there is a limited clinical practice. In fact, early identification of patients
amount of data in this regard on guiding treatment choic- with poor response would allow avoiding ineffective
es. In fact, while it is believed that the available antipsy- treatments and associated adverse effects. Moreover,
chotics have an efficacy that is broadly similar in treat- since some predictive factors can be corrected for, their
ment of schizophrenia 5, they differ significantly in their individuation could provide a specific objective for treat-
adverse event profiles. Given the notable variability in the ment. Lastly, better understanding of factors related to
pharmacokinetics of drugs and response to treatment in response to therapy could help to better comprehend the
individual patients, it is worthwhile highlighting that ef- physiopathology of the disease. However, to date studies
ficacy is generally equivalent between groups of patients, that have attempted to identify factors associated with re-
although this is not necessarily the case when consider- sponse to therapy have been largely negative. Nonethe-
ing the single patient. At present, it is not possible to pre- less, some clinico-demographic variables have been as-
dict which antipsychotic is optimal for any given patient. sociated with pharmacological response, including sex,
There is no drug or dose that is valid for all patients, even duration of disease and duration of untreated disease,
if it seems that there is a dose range for optimal efficacy. age of onset, comorbidity with other psychiatric disorders
Decisions about the choice of antipsychotic often follow and substance abuse 58.
a process of trial and error that includes careful monitor- In recent years, data have emerged that associate differ-
ing of response and adverse effects, prompt evaluation of ences in clinical response to pharmacotherapy in rela-
the risk-benefit ratio and when needed prudent switch to tion to the prevalent clinical dimension of the patient.
another drug 56 (Table V). The available data indicate that the presence of prevalent
In general, typical or first-generation antipsychotics are positive symptoms is associated with good response to
effective in improving positive symptoms, but often cause antipsychotic therapy. A recent study, for example, dem-
motor symptoms or EPS that can be irreversible in the onstrated that response to pharmacological treatment is
case of tardive dyskinesia. The most recent atypical or directly proportional to the severity of positive symptoms,
second-generation antipsychotics can improve both posi- showing that psychotic symptoms respond better to med-
tive and negative symptoms and are less frequently as- ical therapy 59.
sociated with EPS and tardive dyskinesia than first-gen- The negative dimension is more difficult to treat, and if
eration agents. However, weight gain, metabolic altera- prevalent, is associated with poor long-term prognosis 60.
tions and cardiovascular effects are associated with some Olanzapine, aripiprazole and risperidone are more effec-
175
tive than haloperidol in treating the negative symptoms of chotics on cognitive function are generalised or concen-
schizophrenia, confirming data on the greater efficacy of trated on specific areas is still debated 68.
atypical antipsychotics on this dimension 61 62. There is limited information on correlations between de-
The severity of disorganised thought in patients with pression and outcomes in patients with schizophrenia.
schizophrenia is associated with poor long-term prog- The available data suggest that atypical antipsychotics
nosis 63. Moreover, the prevalence of symptoms of dis- are not only not inferior to first-generation antipsychot-
organised thought in patients with schizophrenia is pre- ics in this regard 69, but that at least some (amisulpride,
dictive of response to antipsychotic therapy 64. Disorgan- aripiprazole, clozapine, olanzapine and quetiapine)
ised thought and the positive dimension respond better seem to be more effective in treatment of depression in
to treatment with neuroleptics, even if recent data have schizophrenia 4.
demonstrated that disorganised thought responds better The presence of aggressive impulses is strongly correlated
to atypical antipsychotics 65. with suicidal behaviour in patients with schizophrenia 70.
One of the biggest problems in the treatment of schizo- While aggression is well controlled even by typical anti-
phrenia is recovery or at least maintenance of cognitive psychotics, there is much evidence showing that atypical
function. It is known that the severity of cognitive deficits antipsychotics, and in particular clozapine, improve im-
is one of the most important predictive factors in long- pulsive behaviour and especially self-harm 14.
term outcomes in schizophrenic disorders 66. The avail-
able data are in fair agreement in sustaining that new
Predictable adverse effects of therapy
antipsychotics are more effective than neuroleptics on
cognitive function in schizophrenia 67. It is still unclear, Current guidelines 53 55 recommend that the safety profile
however, to what degree the effects of second-genera- of the drug is a critical factor in the choice of antipsy-
tion antipsychotics have on the cognitive dimension in chotic in patients with schizophrenia. In reality, adverse
schizophrenia, and especially if there are statistically sig- effects of antipsychotics are a crucial aspect of therapy
nificant differences between second-generation agents 68. since they are the major cause of discontinuation of ther-
Moreover, whether or not the effects of atypical antipsy- apy. Adverse effects, therefore, can complicate and un-
Recovery means optimizing individual outcomes
Treatment (reduce symptoms and prevent relapse)

• Antipsychotics and other medications
• Cognitive behavioral therapy
Tratment and other services
Reduce Recovery
Rehabilitation (enhance adaptive skills)
• Social skills training disease
burden Health and wellness
• Vocational and/or
educational functioning
Supports (environmental changes) • Independent living
• Supported housing • Instrumental competence
• Supported employment • Social integration
• Quality of life
Costs and unintended adverse consequences Add

• Side effects • Fiscal costs treatment
• Related health risks • Discrimination
burden
Figure 3.
Healing can be obtained by optimizing individual treatment (from Tandon et al., 2006, modified) . La guarigione può essere
52
ottenuta ottimizzando il trattamento individuale (da Tandon et al., 2006, mod.) 52.
176
table V.
Steps to achieve optimum outcomes with currently available antipsychotics (from Bruijnzeel et al., 2014, modified) 56. Passaggi
per ottenere un outcome ottimale con i farmaci antipsicotici attualmente disponibili (da Bruijnzeel et al., 2014, mod.) 56.
1. Considerations in selecting the best antipsychotic for a particular patient

• Equivalent efficacy across agents
• Individual variability in response
• No good predictor of individual response to different agents
• Different agents have different side effects
• Different patients have different vulnerabilities and preferences
2. Proper antipsychotic trial sequence
• Begin with systematic 6-10 week trial of one antipsychotic with optimal dosing
• If inadequate response, follow with systematic trial of monotherapy with one or more other antipsychotics at adequate dose
and duration
• If inadequate response, follow with a trial of clozapine or a long-acting antipsychotic
• Follow with a trial of clozapine, if not tried before
• Only then consider other strategies (e.g., antipsychotic polypharmacy)
3. Good practice guidelines for ongoing antipsychotic treatment
• Measurement-based individualized care
• Repeated assessment of efficacy using reliably defined treatment targets (facilitated by use of standard rating scales)
• Careful assessment of adverse effects
• Care consistent with health monitoring protocols
• Standard protocols customized to individual vulnerabilities/needs and specific agent
• Ongoing collaboration with patien tin decision-making
table VI.
A summary of the first-generation and second-generation antipsychotic medications (from Xu Q, et al., 2013, modified) 81
.
Riassunto delle caratteristiche dei farmaci antipsicotici di prima e di seconda generazione (da Xu Q, et al., 2013, mod.) 81.
First-generation Second-generation
antipsychotic medications antipsychotic medications
Main content Butyrophenones, Clozapine, olanzapine, risperidone, quetiapine,
phenothiazines thioxanthenes ziprasidone, etc.
Calming effect Powerful Weaker (except clozapine)
Receptor targets Narrow, mainly D2 receptors Multitarget, D2 receptors and serotonin
receptors
High prolactin Common Less common(except risperidone)
Efficacy Good Equivalent or superior
Positive symptoms Good efficacy Good efficacy
Negative symptoms Weaker efficacy Better efficacy
Cognitive symptoms Weaker efficacy Better efficacy
Extrapyramidal symptoms Serious Light
Tardive dyskinesia Common Rare
Effective dose Large dosage Generally small
Compliance Bad Better
Weight gain Obvious More obvious(except ziprasidone)
Metabolic syndrome Common, higher risk Rare, lower risk
177
table VII. table VIII.

Recommendations for the antipsychotic treatment in the acute Recommendations for the antipsychotic treatment in relapse
phase of schizophrenia (from Hasan et al., 2012, modified) 53. phase of schizophrenia (from Hasan et al., 2012, modified) 53.
Raccomandazioni per la scelta del farmaco antipsicotico nella Raccomandazioni per la scelta del farmaco antipsicotico nella
fase acuta della schizofrenia (da Hasan et al., 2012, mod.) 53. recidiva della schizofrenia (da Hasan et al., 2012, mod.) 53.
Antipsychotic agent Category Recommendationb Antipsychotic agent Category Recommendationb

of evidencea of evidencea
Olanzapine A 1 Amisulpride A 1
Quetiapine A 1 Asenapine1 A 1/2
Risperidone A 1 Aripiprazole A 1
Clozapine 1
A 2 Clozapine 2
A 1/2
Haloperidol A 2 Haloperidol A 2
Amisulpride B 2 Iloperidone 1
A 1/2
Aripiprazole B 2 Olanzapine A 1
Ziprasidone B 2 Paliperidone1 A 1/2
Asenapine2 F – Quetiapine A 1
Iloperidone 2
F – Risperidone A 1
Paliperidone2 F – Sertindole1,3 A 1/2
Lurasidone2 F – Ziprasidone A 1
Sertindole 2
F – Lurasidone B 3
Zotepine2 F – Zotepine B 3
a
Category of evidence: Category of evidence where A = full evidence a
Category of evidence: Category of evidence where A = full evidence
from controlled studies. b Safety rating = recommendation grade de- from controlled studies. b Safety rating = recommendation grade de-
rived from categories of evidence and additional aspects of safety, rived from categories of evidence and additional aspects of safety,
tolerability, and interaction potential. 1 Clozapine is highly effective tolerability, and interaction potential. 1 These drugs are not approved
in the treatment of first-episode patients, but because of its side effect for the treatment of schizophrenia in all countries and therefore it
profile it should be considered as recommendation grade 2. 2 It can should be generally considered as recommendation grade 2 in these
be assumed that these antipsychotics are effective in the treatment of countries. 2 Clozapine is highly effective in the treatment of multi-
first-episode schizophrenia, but we could not identify any study to episode patients, but it is only recommended as second line treat-
give an evidence-based recommendation. ment due to its special side-effect profile (see main text). 3 Sertindole
has a safety rating of 1, but due to its cardiovascular side effect profile
the use is restricted in some countries. In these countries, it should be
considered as recommendation grade 2 for legal reasons.
dermine treatment with antipsychotics in various ways.
In fact, adverse effects can cause or worsen the symptoms
associated with schizophrenia, including positive, nega- effects (weight gain, hyperlipidaemia, diabetes) are more
tive, cognitive symptoms and agitation, 71 and can also frequently associated with atypical antipsychotics 75. In
contribute to increased risk for other mental disorders 72. recent years, particular attention has been given to meta-
Lastly, adverse effects are subjectively difficult to toler- bolic adverse effects, also because it has been demon-
ate and can compromise the quality of life. Most adverse
strated that metabolic syndrome is more common in
effects caused by antipsychotics are due to their action
patients with schizophrenia than in the general popula-
on neurotransmitter systems and anatomic regions that
tion. An alternative classification has been proposed for
are different from those involved in their therapeutic ef-
fects 73. Adverse effects are both class- and agent-specific antipsychotics based on metabolic risk, in which they
and are often dose-related: these include neurological, are divided in: a) antipsychotics with high metabolic
cardiovascular, anticholinergic and antiadrenergic effects risk (clozapine, olanzapine, thioridazine, risperidone,
in addition to weight gain, metabolic disorders involving quetiapine); b) antipsychotics with low metabolic risk
glucose and lipids and sexual dysfunction 53 73 (Table XI). (ziprasidone, fluphenazine, haloperidol, aripiprazole,
Adequate treatment of adverse effects, especially during amisulpride). In particular, among atypical antipsychot-
long-term treatment of schizophrenia, can affect adher- ics aripiprazole, ziprasidone and amisulpride have a
ence and therefore improve outcomes 74. Neurological neutral effect on weight gain and lipid metabolism, while
adverse effects such as EPS tend to be more frequently aripiprazole and amisulpride do not increase the risk of
associated with typical antipsychotics, while metabolic developing type 2 diabetes 76.
178
table IX.
Recommendations for the antipsychotic treatment of negative symptoms in schizophrenia (from Hasan et al., 2012, modified) 53.
Raccomandazioni per la scelta del farmaco antipsicotico nel trattamento dei sintomi negativi della schizofrenia (da Hasan et al.,
2012, mod.) 53.
Primary negative symptoms Secondary negative symptoms

Antipsychotic agent Category of evidencea Recommendationb Category of evidencea Recommendationb
Amisulpride A 1 A 1
Asenapine 1
F – B 3
Aripiprazole C3 4 A 1
Clozapine C3 4 A 1
Haloperidol 2
F – A 1
Iloperidone F – F –
Lurasidone F – B 3
Olanzapine A 1 A 1
Paliperidone1 F – A 1
Quetiapine B 3 A 1
Risperidone F – A 1
Sertindole 1,3
F – A 1/2
Ziprasidone B 3 A 1
Zotepine D 5 A 1
Primary negative symptoms are considered a core symptom of schizophrenia, whereas secondary negative symptoms are a consequence of posi-
tive symptoms (e.g. social withdrawal because paranoid ideas), depressive symptoms (e.g. post-psychotic of antipsychotic-induced depression) or
environmental factors (e.g. social understimulation due to hospitalism) (Carpenter et al. 1985). a Category of evidence: Category of evidence where
A = full evidence from controlled studies. b Safety rating = recommendation grade derived from categories of evidence and additional aspects of
safety, tolerability, and interaction potential. 1 These drugs are not approved for the treatment of schizophrenia in all countries and therefore it
should be generally considered as recommendation grade 2 or lower in these countries. 2 Haloperidol is the most commonly used FGA across
all studies. Please see the main text for other FGAs. 3 Sertindole has a safety rating of 1, but due to its cardiovascular side effect profile the use is
restricted in some countries. In these countries, it should be considered as recommendation grade 2 or lower for legal reasons.
Pharmacogenetic and pharmacogenomic data of the dopaminergic system is at the basis of the phys-
iopathology of schizophrenia. Dopamine has different
The basis of individualised medicine consists in the pre- subtypes of receptors (D1 to D5), but only D2, D3 and
supposition that the unique characteristics of an individu- D4 have been extensively studied by pharmacogenetics
al have a significant role in the choice of the most appro- 78 79
. In reality, a number of studies have evaluated the re-
priate therapy. Such characteristics include genetic alter- lationship between response to antipsychotic drugs and
ations and epigenetic modifications, clinical symptoms, genetic variations in dopamine receptors. Another area
modification of biomarkers and environmental factors. of research involves the pharmacokinetics of antipsy-
The objectives of personalised medicine are to predict an chotics, and in particular on the family of cytochrome
individual’s susceptibility to disease, obtain accurate di- P450 enzymes that metabolise most of these drugs.
agnosis and determine efficacy and favourable response Variants in genes that code for these enzymes can lead
to treatment 77. In particular, the aim of pharmacogenet- to an increase or decrease in the metabolism of antipsy-
ics is to predict which patients will benefit from a certain chotics that can alter plasma levels of the drug. In the
drug based on genetic information in order to provide tai- last 15 years, many variants of genes have been studied
lored treatment that will optimise reduction in symptoms in relation to response to antipsychotic drugs 78 79. The
and minimise adverse effects of the drug 78 79. majority of pharmacogenetic studies on antipsychotics
Pharmacogenetic studies are concentrated on the main have investigated selected candidate genes, focusing on
pathways of molecules hypothesised to be involved in polymorphisms in genes that code for receptors of the
the mechanism of action (pharmacodynamics) and on dopamine and serotonin systems, in addition to genes
enzymes that metabolise antipsychotics (pharmaco- that code for enzymes that metabolise antipsychotics
kinetics). It is known since the 1960s that dysfunction such as COMT and CYP2D6 78 79. A number of phar-
179
table X.
Choice of treatment in the acute phase of schizophrenia (from Lehman et al., 2004, modified) 54. Scelta del farmaco nella fase
acuta della schizofrenia (da Lehman et al., 2004, mod.) 54.
Consider Medication From

Patient profile Group 1: Group 2: Group 3: Group 4:
first-generation risperidone, olanzapine, clozapine long-acting
agents quetiapine, ziprasidone, injectable
or aripiprazole antipsychotic
agents
First episode Yes
Persistent suicidal ideation or behavior Yes
Persistent hostility and aggressive Yes
behavior
Tardive dyskinesia Yes; all group 2 drugs may not Yes
be equal their lower or no tar-
dive dyskinesia liability
History of sensitivity to extrapyramidal Yes, except higher doses
side effects of risperidone
History of sensitivity to prolactin Yes, except risperidone
elevation
History of sensitivity to weight gain, Ziprasidone or aripiprazole
hyperglycemia, or hyperlipidemia
Repeated nonadherence to Yes
pharmacological treatment
macogenetic studies have attempted to identify genes many different genes. In addition, it is highly unlikely that
that may be involved in inter-individual differences in a single pharmacological agent can reverse multifacto-
adverse events induced by antipsychotics, although the rial mechanisms associated with neuronal dysfunction
results are inconsistent 78 79. of most processes of the central nervous system with a
Pharmacogenetics involves the use of genomic techniques, complex phenotype that involves mood, personality, be-
such as genotyping, sequencing, gene expression, genetic haviour, cognition and functioning. Treating such a het-
epidemiology, transcriptome, proteomics, metabolome erogeneous clinical picture generally requires the admin-
and bioinformatics to study drugs in clinical use, and ap- istration of a combination of diverse drugs 80.
ply high-throughput systemic approaches to accelerate the
discovery of markers for response to therapy that may be
related to the drug’s target, its metabolism or course of dis- Clinico-pharmacological management
ease 80 81. Pharmacogenomics is different from pharmaco- of the patient with schizophrenia
genetics as the former studies a wide range of genes that A. Fagiolini, A. Altamura, P. Rocca
may be involved in the response to a drug, while the lat-
ter primarily examines specific candidate genes. For many
Introduction
drugs, interindividual differences are mainly due to single
nucleotide polymorphisms (SNP) in genes that code for en- The discovery and development of antipsychotics started
zymes that metabolise or transport drugs and/or are targets more than 50 years ago and has profoundly improved the
of the drug (e.g. enzymes, receptors and defective proteins quality of life of many patients with schizophrenia. As
that alter metabolic pathways, leading to expression of the such, there is little doubt on the benefits (and disadvan-
phenotype of the disease) 80. tages) of antipsychotics 82. Antipsychotic drugs are gener-
The use of these techniques in disorders of the central ally recommended in all phases of schizophrenia, from
nervous system is an extremely complicated process treatment of acute episodes to prevention of relapse 83.
since the majority of neuropsychiatric disorders, includ- The important long-term objectives of treatment plans for
ing schizophrenia, are complex pathologies that involve schizophrenia include improving adherence to therapy,
180
table XI.
Main side effects of typical and atypical antipsychotics (from Marder et al., 2004, modified) 73. Principali effetti collaterali degli
antipsicotici tipici e atipici (da Marder et al., 2004, mod.) 73.
Drug EPS Increased Increased Hyperglycemia Hyperlipidemia QTc Sedation Hypotension Anticholinergic
prolactin weight prolongation effects
Perfenazine ++ ++ + +(?) +(?) + +
Haloperidol +++ +++ + ++
Clozapine +++ +++ +++ +++ +++ +++
Risperidone + +++ ++ ++ ++ + + +
Olanzapine +++ +++ +++ + + ++
Quetiapine ++ ++ ++ ++ ++
Ziprasidone ++
Aripiprazole +*
* Sedation is indicated with higher doses of therapeutic range.
rehabilitation through psychosocial interventions – that less destructive psychotic episodes, while delayed access
involve patients and often even family members – and to mental health services in recent onset schizophrenia
improving the quality of life. A combination of antipsy- seems to be associated with slower and incomplete re-
chotics with other types of intervention is very important covery, increased risk of relapse and poorer prognosis.
in achieving these long-term objectives. Continuity of treatment in the initial phases appears to be
Several important questions regarding pharmacotherapy crucial and can modify long-term prognosis. A study by
of schizophrenia – in particular when to initiate treatment Robinson 64 clearly showed that in spite of a good overall
and how long to continue it – are still unresolved and of- response to initial treatment, patients with a first episode
ten lead to inadequacy of therapy for many patients (e.g. of schizophrenia had a rate of relapse that was > 80%
premature discontinuation or delayed access to pharma- at 5 years. Following initial remission, discontinuation of
cological therapy) 82. Poor adherence to pharmacological the antipsychotic was identified as a significant factor for
therapy is an important aspect that contributes to inad- relapse, increasing the risk by almost 5-fold.
equate treatment 84. Considerable efforts have been made To date only a few controlled clinical trials have evalu-
to improve adherence by developing antipsychotics with ated the possibility of preventing relapse, which is seen
better tolerability in formulations that enable prolonged in 41-79% of cases at 12 months after dose reduction or
administration of the drug, including long-acting inject- discontinuation of treatment 11 (Table XII) in patients with
ables, also known as depot antipsychotics. In recent a first episode of schizophrenia. In one of these studies 86,
years, these formulations of atypical antipsychotics have 131 patients with a first episode in remission for at least
shown promising results in clinical trials that have led 6 months were randomised to gradual discontinuation of
to changes in attitudes towards these drugs, which were therapy or to continue treatment, consisting in the major-
traditionally reserved for patients with recurrent poor ad- ity of cases of low doses of antipsychotics, and followed
herence to treatment 82 85. for 18 months. Discontinuation of therapy was associated
with a significantly higher rate of relapse (43% vs 21%,
p < 0.011). A more recent randomised controlled trial 87
The continuity of treatment
compared the efficacy of additional maintenance therapy
In about 75% of cases, the course of schizophrenia is to intermittent treatment in prevention of relapse in pa-
characterised by a remission phase that alternates with tients with a first episode of schizophrenia in remission
relapses; after the initial episode, it is estimated that only and who had been on maintenance therapy for at least
14-20% of patients can completely recover 83. Moreover, one year. The percentage of relapses was significantly
knowledge of the neurobiological bases of schizophrenia higher in the group receiving intermittent treatment than
has provided evidence regarding the potentially progres- in those undergoing continuous maintenance therapy.
sive nature of the disease. There is clear evidence indi- Both these trials further highlight the importance of con-
cating that interruption of treatment is associated with tinuous maintenance treatment in patients with a first epi-
relapse in the majority of cases 83. In addition, it is in- sode, even after one year in remission.
creasingly evident that early treatment is associated with In light of results that indicate the importance of continu-
181
table XII.
Studies reporting symptom recurrence rates after treatment reduction/discontinuation after a single episode of psychosis (from
Emsley et al., 2013, modified) 11. Studi che riportano le percentuali di recidiva dopo riduzione/sospensione del trattamento a
seguito di un singolo episodio di psicosi (da Emsley et al., 2013, mod.) 11.
Sample Treatment Comparator

Symptom recurrence rates
Authors size duration recurrence rate
9 months 12 months 18 months 24 months 36 months
Kane et al. 28 Not specified 41% 0%
Crow et al. 120 Not specified 62% 46%
Gitlin et al. 53 3 months 78% 96% -
in remission
Wunderink et al. 161 6 months 43% 21%
in remission
Chen et al. 178 12 months + 79% 41%
Gaebel et al. 44 12 months 57% 4%
Boonstra et al. 20 12 months 82% 12%
min remission
Emsley et al. 33 24 months 79% 94% 97% -
ous early treatment, the question can then be asked if long- problem of long-term, continuous antipsychotic treat-
acting antipsychotics (LAI) should be used in first-episode ment is adverse effects. In addition to the well-known
schizophrenia; at present, there are only limited data to neurological adverse effects of antipsychotics, there is
answer this question 88 89. A two-year open-label study 90 good evidence that some atypical antipsychotics are as-
in patients with a first episode of schizophrenia demon- sociated with adverse metabolic effects. Some studies in
strated that those assigned to long-acting risperidone had animal models have suggested that chronic exposure to
a significantly lower rate of relapse and better adherence antipsychotics can contribute to a reduction in the vol-
than those treated with an oral formulation of risperidone. ume of cerebral tissue associated with the disease 94.
In another open-label study 91 on patients with schizo- However, a study 95 carried out in patients with recent
phreniform disorder or schizophrenia at diagnosis, treat- diagnosis showed that prolonged treatment with long-
ment for 2 years with risperidone LAI was associated with acting risperidone was associated with a stable volume
remission in 64% of patients. of white matter, in contrast to a reduction in volume
observed in patients treated with the oral formulation of
Duration of therapy risperidone; the study concluded that modification of ad-
herence with long-acting risperidone may act differently
An open question concerns the optimal means of ensur- on the process of myelinisation, which would explain the
ing continuity of treatment, and in particular for how long better prognosis associated with the long-acting formula-
maintenance treatment should continue in patients with tion compared with the oral formulation.
schizophrenia that is in remission 82. On the basis of clini- It is thus clear that the risk-benefit ratio of long-term treat-
cal evidence and studies demonstrating that a 5-year pe- ment should be carefully evaluated and that care must be
riod following an acute episode represents the period in taken in prescribing the lowest dose of antipsychotic for
which patients are particularly susceptible to relapse, main- effective control of symptoms.
tenance therapy should last for at least 2 to 5 years 92. Ac-
cording to the guidelines of the Canadian Psychiatric Asso-
ciation 93, for treatment of a first psychotic episode antipsy-
Adherence to treatment
chotics should be continued for at least 2 years following One of the main factors that leads to inadequate treat-
the initial remission of symptoms, while a minimum of 5 ment and early discontinuation is poor adherence to
years of stability without relapse and adequate functioning therapy 84. In fact, poor adherence is one of the most
should be observed before considering gradual discontinu- important problems in treatment of patients with mental
ation of the antipsychotic over a period of 6-24 months 74. disorders. The majority of hospital admissions are due to
As in the treatment of other chronic diseases, a relevant non-adherence, even if it is often not clear if non-adher-
182
ence was the cause or consequence of relapse 96. The mulations are used in maintenance treatment of patients
percentage of patients that are partially or completely with schizophrenia, generally following clinical stabilisa-
non-adherent to therapy has been estimated to be be- tion with oral antipsychotics. LAI formulations of atypi-
tween 40% and 60% 97. cal antipsychotics have been developed for risperidone,
The factors that contribute to poor adherence to phar- olanzapine, paliperidone and, more recently, for aripip-
macotherapy for schizophrenia are related to the patient razole: at present, there are 10 LAI formulations, 6 first-
(low insight, depression, substance abuse), treatment generation and 4 second-generation 103.
(adverse effects, poor efficacy, complexity of therapeutic Even if it is reasonable to expect that LAI antipsychot-
regimen) and lack of support or therapeutic alliance with ics can improve adherence to therapy and clinical out-
the medical team 82 98 99 (Table XIII). Some of these fac- comes, the clinical evidence obtained over the years
tors can be overcome by improving the strategies used regarding such benefits is not entirely clear, while the
to administer the drug, such as long-acting formulations. analysis of more recently introduced LAI antipsychotics
However, it should always be considered that for early is in progress. A series of analyses and systematic reviews
recognition and intervention of poor adherence, better has been carried out to indirectly compare the efficacy of
education of patients and training of healthcare providers LAI antipsychotics with oral formulations of both typical
is extremely important. Poor adherence has been identi- and atypical antipsychotics 104-108.
fied as an important risk factor for relapse 84 100. The use A large systematic meta-review 104, covering 8 Co-
of LAI antipsychotics has been demonstrated to improve chrane reviews of randomised clinical trials of individ-
adherence to therapy, and is associated with fewer treat- ual typical LAI antipsychotics in patients with schizo-
ment discontinuations, relapses and hospitalisations 101. phrenia or schizophreniform disorder showed that the
rates of relapse and tolerability profiles are similar for
oral and LAI formulations, while general clinical im-
Typical and atypical antipsychotics provement was significantly higher for LAI compared
Even if atypical antipsychotics are widely used, there with oral formulations.
is continued debate regarding their tolerability, which A recent systematic review 105, including studies with
is presumed to be better than first-generation agents. different designs and comparing typical LAI antipsy-
In recent years, the propensity of atypical antipsychot- chotics with atypical oral formulations, indicated that
ics to induce weight gain and metabolic alterations in the LAI antipsychotics had greater clinical benefit than
glucose and lipids has raised doubts about their ad- oral formulations, although the results were variable
vantages over typical antipsychotics. For this reason, and inconclusive mainly because of the heterogeneity
the role of some atypical antipsychotics in treatment of in methods and interventions used in the various stud-
schizophrenia has been reconsidered. Taken together, ies. In addition, a recent publication 109 confirmed that
the results of recent analyses comparing typical and studies using different methodologies may give different
atypical antipsychotics has demonstrated a high lev- results, and that studies on LAI antipsychotics may be an
el of heterogeneity between the two classes of drugs example of a situation where conventional randomised
that does not allow for any general conclusions to be trials may not be the gold standard: in fact, these types
drawn. The choice of drug should thus be made on of studies tend to increase adherence to treatment and
an individualised basis considering the available thera- therefore lead to underestimation of the possible ben-
peutic options 53 74 83 102. efits of LAI antipsychotics compared with the corre-
sponding oral formulations. A significant reduction in
the rates of relapse (21.6% vs 33.3%, RR 0.70, 95% CI
Long-acting injectable antipsychotics (LAI)
0.57-0.87, p = 0.0009) and dropouts for inefficacy of
LAI antipsychotics were introduced over 40 years ago be- typical LAI antipsychotics compared to oral antipsy-
cause of their numerous potential advantages over oral chotics was reported in a systematic review and meta-
formulations, including the possibility to monitor com- analysis of 10 long-term RCT lasting at least 12 months
pliance and distinguish poor adherence from lack of re- published between 1975 and 2010, for a total of 1,700
sponse, regular contact with the patient and caregiver, outpatients 106.
reduced risk of accidental or deliberate overdose, better Another systematic review of studies published between
bioavailability and more predictable correlation between 2000 and 2011 107 compared the efficacy of LAI and oral
dose and plasma levels 97. antipsychotics on relapse, hospitalisation and all-cause
However, LAI antipsychotics have several limitations discontinuation of therapy in schizophrenia revealed a
such as slow dose titration, longer time to reach steady clear difference between observational studies (4 pro-
state levels and sustained adverse effects if discontinued spective and 4 retrospective), which showed a significant
for problems related to tolerability. Traditionally, LAI for- advantage for LAI formulations (prospective: RR = 0.62,
183
table XIII.
Factors associated with non-adherence (from Kane et al., 2013, modified) 99. Fattori associati con la mancata aderenza (da Kane
et al., 2013, mod.) 99.
Patient characteristics Provider/system/treatment

Sex, age, race characteristics (continued)
Education Duration of treatment (past and expected)
Socio-economic status Complexity of administration
Knowledge Accessibility and cohesion of services
Perceived need for treatment (insight) Access to care
Motivation Continuity of care
Beliefs about treatment risks and benefits Reimbursement
Past experiences/“transference” Ability to monitor adherence
Past history of adherence Provision of psychoeducation
Self-stigma Availability of trained psychosocial treatment
specialists
Illness characteristics Evaluation of obstacles to adherence
Illness duration (first episode, chronic) Access to alternative formulations (e.g., long-acting
Illness phase (acute, maintenance, etc.) injectable antipsychotics)
Symptom type and severity (e.g., negative Complexity of administration
symptoms, depression, demoralization)
Cognitive function Family/caregiver characteristics
Lack of insight Nature of relationship
Substance use Perceived need for treatment (insight)
Comorbidities Beliefs about treatment risks and benefits
Degree of refractoriness Knowledge, beliefs, attribution
Potential for relatively asymptomatic intervals or Involvement in psychoeducation
“spontaneous remission” Involvement in adherence monitoring
Stigma
Medication characteristics Environmental characteristics
Efficacy (consider different domains) Physical environment
Effectiveness Level of supervision
Adverse effects (of relevance for the patient) Orderliness
Delivery systems/formulation Safety and privacy
Dosage frequency Stigma
Cost/access Extrafamilial support system
Provider/system/treatment characteristics Other resource characteristics

Therapeutic alliance Financial
Frequency and nature of contact with clinicians Transportation
95% CI 0.48-0.81, p < 0.001; retrospective: RR = 0.56, chotics. It was found that LAI antipsychotics were more
95% CI 0.44-0.71, p < 0.001), and randomised con- effective than placebo [p < 0.001 for PANSS (positive and
trolled studies (5 trials), which showed a non-significant negative syndrome scale) score] and at least as effective
difference favouring LAI formulations (RR = 0.89, 95% CI and safe than oral antipsychotics.
0.64-1.22, p = 0.416) (Fig. 4). The authors of this meta-
analysis concluded that in this type of comparison the
Efficacy and safety of individual LAI
trial design can considerably influence the results, prob-
antipsychotics
ably since controlled clinical studies, even if avoiding
confounding factors and possible selection bias associ- For risperidone LAI, despite studies that have demonstrat-
ated with observational studies, are not reflective of a ed significant reduction in relapse with LAI formulations
real-world treatment setting. over oral formulations, other studies have not confirmed
A meta-analysis of 13 randomised trials on 6,313 pa- this superiority 82 106 110 111. It is likely that the differences in
tients 108 compared efficacy and safety of second-gen- results are related to dissimilarities in the quality, design
eration LAI antipsychotics to placebo and oral antipsy- and methodologies of various studies 82.
184
Study Favors Depot Favors Oral RR 95% CI Weight
RCTs
Gaebel et al., 2010 0.58 0.39-0.86 15.13
Gaebel et al., 2010 0.50 0.38-0.67 17.14
Kane et al., 2010 2.03 1.31-3.16 14.38
Keks et al., 2007 0.92 0.72-1.18 17.77
Macfadden et al., 2010 1.07 0.84-1.37 17.76
Rosenheck et al., 2011 0.89 0.70-1.13 17.82
Pooled RCTs 0.89 0.64-1.22
Prospective studies
Ciudad et al., 2008 0.80 0.60-1.06 24.18
Kim et al., 2008 0.30 0.14-0.67 8.15
Olivares et al., 2009 0.52 0.43-0.64 28.07
Olivares et al., 2009 0.89 0.57-1.39 17.07
Zhu et al., 2008 0.59 0.43-0.81 22.53
Pooled prospective studies 0.62 0.48-0.81
Retrospective studies
Emsley et al., 2008 0.25 0.09-0.70 5.02
Emsley et al., 2008 0.38 0.22-0.64 15.06
Tavcar et al., 2000 0.71 0.49-1.01 26.45
Tiihonen et al., 2006 0.61 0.38-0.99 17.91
Tiihonen et al., 2011 0.16 0.02-1.05 1.53
Tiihonen et al., 2011 0.69 0.35-1.35 10.48
Tiihonen et al., 2011 0.46 0.16-1.34 4.66
Tiihonen et al., 2011 0.64 0.41-1.02 18.89
Pooled retrospective studies 0.56 0.44-0.71
0.01 0.10 1.00 10.00

Adjusted Relative Risk (log scale)
Hospitalization Relapse All-cause discontinuation
RCT: randomized controlled trial; RR: risk ratio.
Figure 4.
Meta-analysis of adjusted risk ratios, by study design (from Kirson et al., 2013, modified) 107
. Meta-analisi del rischio relativo
standardizzato, a seconda del disegno dello studio (da Kirson et al., 2013, mod.) 107.
The efficacy and tolerability of olanzapine LAI (olanzap- the PANSS score in patients with symptomatic acute
ine pamoate) has been investigated in two randomised, schizophrenia or in delaying the appearance of relapse
double-blind, studies, one versus placebo 112 and the oth- in patients with stable disease 114 115. Paliperidone LAI
er versus oral olanzapine 113. In the former, olanzapine has been demonstrated to have a metabolic profile simi-
was found to be significantly more effective that placebo lar to other second-generation antipsychotics; more-
in reducing the PANNS score, but with weight gain and over, as in the case of olanzapine LAI and risperidone
alterations in lipid metabolism. The second study dem- LAI, its use has been associated with worsening of psy-
onstrated the efficacy of olanzapine LAI in maintenance chosis in some patients 116.
treatment up to 24 weeks. More recently, the EMA has approved aripiprazole LAI
Several studies have demonstrated that paliperidone LAI for maintenance treatment of schizophrenia in adult pa-
(paliperidone palmitate) is more efficacious than place- tients stabilised with oral aripiprazole 117. The clinical
bo and is non-inferior to risperidone LAI in improving efficacy of aripiprazole LAI has been established in two
185
randomised, double-blind clinical studies in patients seen in 6.4% of patients treated with aripiprazole LAI
with schizophrenia. In the first 118, aripiprazole LAI was and 5.2% of subjects in the placebo group; weight loss ≥
shown to be non-inferior to oral aripiprazole consider- 7% was seen in 6.4% in the aripiprazole LAI group and
ing both the rate of relapse after 26 weeks and improve- 6.7% of patients in the placebo group; the mean change
ments in the PANSS score. In a previous study 119, ar- in weight from baseline to last visit was -0.2 kg for LAI
ipiprazole LAI was associated with a risk of relapse at and -0.4 kg for placebo (p = 0.812).
52 weeks that was 5.03 fold lower than placebo. The
most common adverse events observed in the two stud-
Quality of life, functioning and treatment
ies were: weight gain (9.0%), motor symptoms (7.9%),
satisfaction of patients with LAI antipsychotics
insomnia (5.8%) and injection site pain (5.1%). In par-
ticular, injections site reactions were generally mild to Quality of life is an important parameter in evaluating
moderate and self-limiting; injections site pain appeared the benefits of treatment, especially in chronic diseases.
at a median of 2 days after injection and lasted for a me- Studies that have examined patients switching from an
dian of 4 days. Aripiprazole LAI was associated with a oral to LAI formulation of an antipsychotic have reported
greater frequency of EPS (18.4 %) than oral aripiprazole significant improvements in the quality of life, overall
(11.7%); motor symptoms were the most frequent ad- functioning and treatment satisfaction 101.
verse effect and generally appeared around 10 days af- In one study, following unsatisfactory treatment with
ter the first injection and lasted for a median of 56 days, oral antipsychotics, 182 patients with schizophrenia
while Parkinsonism was slightly less frequent (6.9%). were switched to a LAI antipsychotic for 6 months 120.
In the study by Fleischhacker 118, weight gain ≥7% vs Compared to baseline, over the 6-month observation
baseline and last visit was 9.5% in the group treated period significant improvement (p < 0.05) was seen in
with aripiprazole LAI and in 11.7% the oral aripiprazole the PANSS score. Moreover, significant improvement
group; weight loss ≥7% from baseline values to last visit (p < 0.05) was seen in Global Assessment of Function-
was seen in 10.2% of patients treated with aripiprazole ing, health-related quality of life and patient satisfac-
LAI and 4.5% of patients in the aripiprazole oral group. tion. The effects of LAI on functional improvements
In a previous study by Kane 119, weight gain ≥ 7% was and quality of life were also evaluated in a placebo-
table XIV.
Decision algorithm for choosing a long-acting antipsychotic based on treatment compliance predictors reported in the literature
(from Rossi et al., 2012, modified) 124. Algoritmo decisionale per scegliere un antipsicotico LAI basandosi sui fattori predittivi di
compliance al trattamento riportati in letteratura (da Rossi et al., 2012, mod.) 124.
Good compliance Poor compliance

Late Age at onset Young
Long Lenght of illness Short
Yes Insight No
Mild Positive and negative symptoms Severe
No Drug abuse Yes
Low Percentage of relapse High
Low Frequency of hospitalizations High
Oral Ongoing therapy Oral/depot
No Previous depot Yes
Evaluate patient’s interest in taking depot Evaluate patient’s interest in switching to

treatment considering: atypical depot. Considering:
• Insight of illness severity • Severity of illness
• Educational level • Dosages of ongoing therapy
• Therapeutic alliance • Efficacy profile of the depot
• Possibility of sharing the therapeutic
decision with the physician
186
A B
General open-ended question

Probes for adherence, tolerability,
and patient response
symptoms, and treatment assessment*
“What would you like to talk about?”
Prescriber-managed
Managed mutually by SW/therapist and patient
Patients may offer subjective

illness narrative
Life and living skills
Patients may express • Probes on negative symptoms and social outcomes

treatment preferences • May check medication adherence
• Discuss finances/money management
Patient-managed on prescriber invitation • Discuss family life and review practical living skills
SW/therapist-managed
Treatment planning and LAI

scheduling (if chosen)
(Based on patient status, adherence Goal setting and therapy planning
and tolerance) “What would you like to work on?”
Prescriber-managed Managed mutually by SW/therapist and patient
FigurE 5.
Observed conversation flow between: A) patients and prescribers (n = 69); B) patients and social workers or therapists (from Potkin
et al., 2013, modified) 128. Flusso di conversazione osservato tra: A) pazienti e prescrittori; B) pazienti e terapisti sociali (da Potkin
et al., 2013, mod.) 128.
controlled, randomised, double-blind, 8-week study Current uses and guidelines for LAI
on 404 outpatients with schizophrenia 121. Significant antipsychotics
(p < 0.01) improvement was seen with a LAI formula-
tion compared to placebo in the quality of life and in Current guidelines 53 74 83 92 93 generally recommend LAI
the Short Form Health Survey. Macfadden et al. 122 as- antipsychotics for maintenance therapy, among the other
sessed the efficacy of a LAI formulation on the quality options for maintenance therapy, and/or when better ad-
of life and functioning in an observational, prospective herence is needed. According to the guidelines, LAI can
24-month study on 532 patients with schizophrenia. even be considered in the acute phase of schizophrenia
After initiation of therapy with a LAI, patients reported if there is repeated lack of adherence or poor adher-
improvement at 3 months that continued throughout the ence 92 124, while the data on the use of new LAI formula-
24-month follow-up period. Improvements were seen in tions in patients with a first episode are considered to be
Global Assessment of Functioning, Strauss-Carpenter too limited to allow any specific recommendations (Ta-
Levels of Functioning, Personal and Social Performance ble XIV). However, many experts feel that the guidelines
and overall health. The Switch To Risperidone Micro- are too conservative and that the position of LAIs in treat-
spheres trial 123 was carried out in patients with schizo- ment of schizophrenia should be reconsidered 96. With
phrenia who were switched from an oral antipsychotic the increase in information on the efficacy and tolerabil-
or first-generation LAI to a second-generation LAI for ity of atypical LAI antipsychotics, international guidelines
lack of efficacy, adverse effects, or poor adherence. Af- should be updated regarding the different phases of dis-
ter 6 months, improvements vs baseline were seen with ease in which LAIs can be recommended and on the pa-
the second-generation LAI for symptoms, global func- tients who could benefit from their administration.
tioning, quality of life, treatment satisfaction and rate of Other data that has emerged from studies carried out in
hospitalisation. several Western countries, including Italy, concerns the
187
LAI therapy discussed LAI therapy not discussed
Positive Approach: Punitive Approach:

• Benefits of LAIs • Address compliance
Therapy introduced via:
• Success stories of other problems
patients • Scare tactics/threats
Patient response Favorable Neutral Resistant/Concerned
HCP responds to
patient resistance Decompose resistance
Step may be skipped Emphasize benefits • Uncover severity of
Abandon discussion
if resistance is not of LAIs resistance
expressed • Overcome objections
Patient acceptance
Prescriber selects the Patient accepts LAI Patient does not accept
specific LAI without patient therapy LAI therapy
or caregiver input
Ideal conversation path LAI initiation barrier
FigurE 6.
Observed conversation decision tree for prescriber interactions with patients regarding initiation of long-acting injectable
antipsychotics (from Potkin et al., 2013, modified) 128. Albero decisionale delle conversazioni osservate nelle interazioni con i
pazienti riguardo all’inizio di una terapia con antipsicotici LAI (da Potkin et al., 2013, mod.) 128.
relatively low use of LAIs even in patients who could favourable therapeutic strategy even from an economical
clearly benefit from them. This can be explained by a standpoint.
number of misunderstandings and prejudices among
prescribers, patients and caregivers for LAI formulations, Practical recommendations on the use
which are considered older drugs, that are forced upon
of atypical LAI antipsychotics
patients, reserved for those with poor adherence, and as-
sociated with adverse events and reduced involvement There is broad consensus among specialists that the op-
of healthcare personnel in the care of psychiatric pa- timal use of new LAI formulations requires substantial
tients 125. Some psychiatrists consider LAIs as a ‘last re- changes in the general attitudes towards treatment with
source’ of treatment, which should be used only when depot antipsychotics 82 96. LAI antipsychotics should be uti-
all other pharmacotherapies have failed, and reserved for lised for any patient undergoing long-term treatment, and
patients who have presented with multiple episodes. not only for those with problems in adherence 83 96 126. Effec-
The high cost of LAI antipsychotics is another relevant tive maintenance therapy can be considered as a starting
barrier to increased prescribing of these formulations 106. point that leads to successful multimodal treatment pro-
However, recent pharmacoeconomic studies have grammes and rehabilitation. Since it is believed that oral
shown that atypical LAI antipsychotics can represent a antipsychotics should be initiated in patients with a new
188
diagnosis of schizophrenia 83, even if data on the efficacy as a speaker on symposia for Angelini, AstraZeneca, Bristol-
of LAI antipsychotics are still limited, it can be expected Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen-Cilag,
that these formulations will also be favourable compared Lundbeck, Novartis, Otsuka, Pfizer, Roche.
with oral antipsychotics in this setting. In patients with Silvana Galderisi has received grant/research and/or has
collaborated as consultant and/or speaker in symposia for Janssen-
acute exacerbations of schizophrenia, in which the guide-
Cilag, Roche, Otsuka, Lundbeck, Pierre Fabre e Amgen-Dompé.
lines recommend treatment with oral antipsychotics, when
Paola Rocca has participated as speaker on symposia for Bristol-
the exacerbation is due to repeated non-adherence to poor Myers Squibb, Janssen-Cilag, Otsuka, Roche.
adherence, the use of a LAI antipsychotic is advised 82. Alessandro Rossi has received grant/research and/or has
Switching from an oral to LAI formulation requires precise collaborated as consultant and/or speaker in symposia for
strategies to maintain or improve therapeutic efficacy and Takeda, Roche, Lundbeck, Janssen-Cilag.
minimise rebound cholinergic or histaminergic effects 127.
In conclusion, the recent development of LAI formulations
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Editorial Note: Please refer to the SPC (Summary of Product Characteristics) of each
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Integrated Treatment of Schizophrenia: Il Trattamento Integrato Della Schizofrenia

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Dimensional psychopharmacology

Integrated treatment of schizophrenia

Summary It has been made a considerable effort to improve adherence

Pharmacological treatment, rehabilitative Thus, the psychiatrist should be part of a multidisciplinary

168 Journal of Psychopathology 2015;21:168-193

non-adherent to oral therapy 19, even if this percentage

50 • lack of improvement of psychotic symptoms;

Evidence-based approaches Promising approaches

Intervention Potential benefits

that ‘recall sessions’ in a multifamily setting may be use- 50

Individualisation of treatment second-generation antipsychotics (clozapine, olanzap-

Recovery means optimizing individual outcomes

Treatment (reduce symptoms and prevent relapse)

Costs and unintended adverse consequences Add

1. Considerations in selecting the best antipsychotic for a particular patient

table VII. table VIII.

Antipsychotic agent Category Recommendationb Antipsychotic agent Category Recommendationb

Primary negative symptoms Secondary negative symptoms

Consider Medication From

Sample Treatment Comparator

Patient characteristics Provider/system/treatment

Provider/system/treatment characteristics Other resource characteristics

Study Favors Depot Favors Oral RR 95% CI Weight

0.01 0.10 1.00 10.00

RCT: randomized controlled trial; RR: risk ratio.

Good compliance Poor compliance

Evaluate patient’s interest in taking depot Evaluate patient’s interest in switching to

General open-ended question

Patients may offer subjective

Life and living skills

Patients may express • Probes on negative symptoms and social outcomes

Treatment planning and LAI

LAI therapy discussed LAI therapy not discussed

Positive Approach: Punitive Approach:

Patient response Favorable Neutral Resistant/Concerned

Ideal conversation path LAI initiation barrier

ophrenia: core interventions in the treatment and manage-

Bond GR, Drake RE, Becker DR. Generalizability of the In-

2012;13:318-78. improvement after treatment with second-generation antip-

www.nice.org.uk/guidance/cg178. related to suicide attempts in schizophrenic patients: a ret-

phrenia: systematic review of randomised controlled trials 118

With the non conditioned contribution of Otsuka Pharmaceutical Italy Srl

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