Use of antipsychotics in the treatment of depressive disorders

Summary： There is a long history of using antipsychotic medications in the treatment of depressive disorders. Atypical antipsychotics, which have fewer side effects than traditional antipsychotics, have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical ant-ipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid （GABA）, cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration （USFDA） has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment- resistant depression. When using atypical ant-ipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects including extrapyramidal symptoms （EPS）, weight gain, and hyperglycemia.     

Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice

Second-generation antipsychotics (SGA) are being used more often than ever before in children and adolescents with psychotic and a wide range of non-psychotic disorders. Several SGA have received regulatory approval for some paediatric indications in various countries, but off-label use is still frequent. The aim of this paper was to perform a systematic review and critically evaluate the literature on cardiometabolic and endocrine side-effects of SGA in children and adolescents through a Medline/Pubmed/Google Scholar search of randomized, placebo controlled trials of antipsychotics in children and adolescents (<18 years old) until February 2010. In total, 31 randomized, controlled studies including 3595 paediatric patients were identified. A review of these data confirmed that SGA are associated with relevant cardiometabolic and endocrine side-effects, and that children and adolescents have a high liability to experience antipsychotic induced hyperprolactinaemia, weight gain and associated metabolic disturbances. Only weight change data were sufficiently reported to conduct a formal meta-analysis. In 24 trials of 3048 paediatric patients with varying ages and diagnoses, ziprasidone was associated with the lowest weight gain (−0.04 kg, 95% confidence interval [CI]: −0.38 to +0.30), followed by aripiprazole (0.79 kg, 95% CI: 0.54 to 1.04], quetiapine (1.43 kg, 95% CI: 1.17 to 1.69) and risperidone (1.76 kg, 95% CI: 1.27 to 2.25) were intermediate, and olanzapine was associated with weight gain the most (3.45 kg, 95% CI: 2.93 to 3.97). Significant weight gain appeared to be more prevalent in patients with autistic disorder who were also younger and likely less exposed to antipsychotics previously. These data clearly suggest that close screening and monitoring of metabolic side effects is warranted and that the least cardiometabolically problematic agents should be used first whenever possible. A good collaboration between child- and adolescent psychiatrists, general practitioners and paediatricians is essential to maximize overall outcomes and to reduce the likelihood of premature cardiovascular morbidity and mortality.     

Second-generation antipsychotic medications in children and adolescents

OBJECTIVE: We reviewed available pediatric literature on second-generation antipsychotic medications to assess current evidence of efficacy and safety. METHOD: An English language MEDLINE search (1974-2003) was conducted using key words-atypical antipsychotics, children and adolescents, toxicity, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Additional efficacy and safety data were obtained from drug manufacturers. RESULTS: We identified 176 reports, including 15 double-blind, controlled trials, 58 openlabel studies, 18 retrospective chart reviews, and 85 case series/reports. The majority of these studies (43%) were of risperidone. Evidence suggests that second-generation antipsychotics are efficacious in the treatment of psychosis, bipolar disorders, pervasive developmental disorders, and Tourette's Disorder, and are potentially useful in mental retardation, conduct disorder, and severe attention deficit hyperactivity disorder (ADHD). The most frequently reported side effects included cardiovascular effects, weight gain, sedation, sialorrhea, extrapyramidal signs, and hyperprolactinemia, although the relative frequencies of these untoward effects vary among medications. CONCLUSION: Although the evidence base for pediatric use of second-generation antipsychotics is expanding, the majority of available studies are anecdotal, or short-term, openlabel trials. Reports suggest that these compounds are effective for a variety of psychiatric disorders in children and adolescents, but additional double-blind, controlled studies are required to establish definitive efficacy. Although these medications appear to be well tolerated in short-term studies, long-term follow-up investigations and ongoing clinical monitoring are necessary to confirm their safety in this age group.     

Evidence Base for Using Atypical Antipsychotics for Psychosis in Adolescents

Atypical antipsychotic medications have been the first line of treatment for adolescents with psychosis in the past couple of decades. Till the late 90s, there were very few randomized controlled trials (RCTs) on the treatment of adolescents with psychosis, although a fifth of schizophrenia starts during adolescence. Most of the treatment guidelines for adolescents with psychosis were derived from data on adults. In the past 10 years, there has been increasing number of studies on adolescents with psychosis. The current paper summarizes the findings of trials on adolescents with psychosis in 4 groups: (a) atypical antipsychotic medications vs placebo, (b) atypical antipsychotic medication vs typical antipsychotic medications, (c) one atypical antipsychotic medication vs another atypical antipsychotic medication, and (d) Low dose vs standard dose of atypical antipsychotic medication. We included 13 RCTs, with a total of 1112 participants. Although our review suggest that atypical antipsychotic medications are as effective as typical antipsychotic medications as regards clinical efficacy, atypical antipsychotic medications have a preferred side effect profile and lesser drop-out rate from trials. Obviously, this is extremely important as treatment adherence is key to successful remission of psychotic symptoms and also in some case prevent relapse of illness. Treatment with olanzapine, risperidone, and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidemia. Adolescents may respond better to standard-dose as opposed to lower dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trial should be longer term and have uniform ways of reporting side effects.Key words: atypical antipsychotic, medications, adolescents, psychosis, systematic review, meta-analysis, young people, pharmacology, schizophrenia     

Olanzapine response in psychotic depression

BACKGROUND: Psychotic depression is more common than is generally realized, occurring in an estimated 16% to 54% of depressed patients. In controlled studies of patients with schizophrenia, the atypical antipsychotic olanzapine has been shown to be superior in efficacy to haloperidol at doses of 10 mg/day. Since olanzapine may have antidepressant effects in addition to its antipsychotic properties, the purpose of this study was to assess the safety and efficacy of olanzapine in the treatment of psychotic depression. METHOD: Hospitalized patients with the discharge diagnosis of DSM-IV psychotic depression (major depression with psychotic features or bipolar I disorder, depressed phase...with psychotic features) who had been treated with olanzapine during the first 9 months of its availability in the United States were identified. An age- and sex-matched sample of hospitalized patients with psychotic depression treated with other antipsychotics during the same time period was also identified. The medical records were expunged of all references to medication treatment and then reviewed and scored in a blind fashion for indications, doses, response, and side effects. RESULTS: Fifteen psychotic depression patients (10 women, 5 men), aged 36.9 +/- 10.1 years, who were treated with olanzapine were retrospectively compared with 15 psychotic depression patients (10 women, 5 men), aged 35.0 +/- 8.2 years, treated with other antipsychotics. Ten (67%) of 15 patients taking olanzapine were much or very much improved upon discharge compared with only 4 (27%) of 15 patients taking other antipsychotics (Fisher exact test, p = .037). Olanzapine was well tolerated: no patient discontinued the medication because of side effects. Twelve (80%) of 15 patients in each group were taking antidepressants in addition to the antipsychotic. Of the 3 patients taking olanzapine but not taking an antidepressant, 2 were much or very much improved (1 patient taking olanzapine alone, 1 taking olanzapine plus valproate sodium). CONCLUSION: Olanzapine appears to be effective and safe for patients with psychotic depression. Further prospective studies are warranted to ascertain whether olanzapine's unique pharmacologic profile may make it particularly useful for the treatment of psychotic depression either alone or in combination with antidepressants.     

Open-label, prospective trial of olanzapine in adolescents with subaverage intelligence and disruptive behavioral disorders

OBJECTIVE: Olanzapine, an atypical antipsychotic, has been shown to be efficacious for treatment of psychotic and mood disorders in adults. This prospective, open-label study was conducted to examine the safety and usefulness of olanzapine in treating disruptive behavior disorders in adolescents with subaverage intelligence. METHOD: Sixteen adolescents (ages 13-17 years) with borderline to moderate mental retardation and disruptive behavior were enrolled in an 8-week olanzapine trial (5-20 mg/day). Dependent measures included the Aberrant Behavior Checklist, Conners Parent Rating Scale, Clinical Global Impressions, and two side effects scales. RESULTS: Statistically significant improvement (p <.002) was found on the Irritability and Hyperactivity subscales of the Aberrant Behavior Checklist and the Conners Parent Rating Scale Hyperactivity Index. No subjects developed extrapyramidal side effects. However, four were terminated prematurely from the trial because of either worsening of symptoms (requiring psychiatric inpatient hospitalization in two subjects) or side effects. The most common side effect for the sample was weight gain (averaging 12.7 lb), with 67% of subjects gaining > or =10 lb. Although there was also a statistically significant increase in prolactin levels, no subjects reported prolactin-related side effects (e.g., gynecomastia, galactorhea, amenorrhea). CONCLUSION: Olanzapine may be useful in treating disruptive behavior in adolescents with subaverage intelligence. However, side effects, especially weight gain, are a significant issue. Future double-blind, placebo-controlled studies need to confirm these findings and assess long-term safety and outcome of olanzapine treatment.     

First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis

BACKGROUND: The increased prevalence of diabetes in schizophrenia is partly attributed to antipsychotic treatment, in particular second-generation antipsychotics, but the evidence has not been systematically reviewed. AIMS: Systematic review and meta-analysis comparing diabetes risk for different antipsychotics in people with schizophrenia. METHOD: We searched MEDLINE, PsycINFO, EMBASE, International Pharmaceutical Abstracts, CINAHL and Web of Knowledge until September 2006. Studies were eligible for inclusion if the design was cross-sectional, case-control, cohort or a controlled trial in individuals with schizophrenia or related psychotic disorders, where second-generation antipsychotics (defined as clozapine, olanzapine, risperidone and quetiapine) were compared with first-generation antipsychotics and diabetes was an outcome. Data were pooled using random effects inverse variance weighted meta-analysis. RESULTS: Of the studies that met the inclusion criteria (n=14), 11 had sufficient data to include in the meta-analysis. Four of these were retrospective cohort studies. The relative risk of diabetes in patients with schizophrenia prescribed one of the second-generation v. first-generation antipsychotics was 1.32 (95% CI 1.15-1.51). There were insufficient data to include aripiprazole, ziprasidone and amisulpride in this analysis. CONCLUSIONS: There is tentative evidence that the second-generation antipsychotics included in this study are associated with a small increased risk for diabetes compared with first-generation antipsychotics in people with schizophrenia. Methodological limitations were found in most studies, leading to heterogeneity and difficulty interpreting data. Regardless of type of antipsychotic, screening for diabetes in all people with schizophrenia should be routine.     

Antipsychotic Agents in the Treatment of Anorexia Nervosa: Neuropsychopharmacologic Rationale and Evidence from Controlled Trials

The search for an effective psychopharmacologic strategy in the treatment of anorexia nervosa (AN) has been elusive for decades and has run the gamut from reserpine to typical antipsychotics, to lithium, to tetrahydrocannabinol, to growth hormone, to anticonvulsants, to antidepressants, to atypical antipsychotics. Only recently has there arisen a potential "diamond in the rough" in the form of the atypical antipsychotic agent, olanzapine, which, in four randomized clinical trials, has shown superiority to placebo (two studies), chlorpromazine (one study), and aripiprazole (one study) in terms of weight gain and/or reduction in obsessional symptoms. The pharmacologic profile of olanzapine and other antipsychotic medications is discussed in light of the known pathophysiology of AN involving serotonin and dopamine systems, as well as brain-derived neurotrophic factor.     

Comparative efficacy of typical and atypical antipsychotics as add-on therapy to mood stabilizers in the treatment of acute mania.

BACKGROUND: Typical antipsychotics are commonly used in combination with mood stabilizers for acute mania. Although typical antipsychotics are effective, they have undesirable side effects such as induction of depressive symptoms and tardive dyskinesia. Atypical antipsychotics have more favorable side effect profiles, and recent evidence shows their efficacy in treating mania. Apart from a previous small study that compared risperidone with typical neuroleptics as add-on therapy to mood stabilizers, no studies to date have directly compared atypical antipsychotics with typical antipsychotics as add-on therapy to mood stabilizers in a clinically relevant, naturalistic setting. METHOD: This study is a chart review of all patients with DSM-IV-defined bipolar disorder, current episode mania (N = 204), admitted to the University of British Columbia Hospital during a 30-month period. Patients were separated into 3 groups according to the medications used: (1) mood stabilizer and typical antipsychotic, (2) mood stabilizer and atypical antipsychotic, and (3) combination: mood stabilizer plus a typical antipsychotic, then switched to mood stabilizer plus risperidone or olanzapine within I week. The atypical group was further subdivided into risperidone and olanzapine subgroups. Outcome was measured using Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) ratings generated by review of clinical information in the chart. RESULTS: Patients treated with typical antipsychotics were more severely ill at admission and at discharge than those treated with atypical antipsychotics. Patients in the atypical (p < .005) and combination (p < .05) groups showed significantly greater clinical improvement at discharge than patients treated with typical antipsychotics. This difference was also significant in the subset of patients with psychotic features (p < .03). Risperidone and olanzapine were associated with fewer extrapyramidal side effects than were typical antipsychotics (risperidone vs. typical antipsychotics, chi2 = 8.72, p < .01; olanzapine vs. typical antipsychotics, chi2 = 16.9, p < .001). CONCLUSION: Due to their superior effectiveness and side effect profile when compared with typical antipsychotics. atypical antipsychotics are an excellent choice as add-on therapy to mood stabilizers for the treatment of patients with mania.     

Metabolic effects of second‐generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses

Moreno C, Merchán‐Naranjo J, Álvarez M, Baeza I, Alda JA, Martínez‐Cantarero C, Parellada M, Sánchez B, de la Serna E, Giráldez M, Arango C. Metabolic effects of second‐generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses.
Bipolar Disord 2010: 12: 172–184. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Despite known metabolic effects of second‐generation antipsychotics (SGAs) on children and adolescents, comparative effects in youth with different diagnoses remain underreported. We compared differences in metabolic changes three months after starting treatment with SGAs in youth with bipolar disorder and with other psychotic and nonpsychotic disorders. Methods: Weight and metabolic differences among diagnostic groups before and three months after starting treatment with SGAs were compared in a naturalistic cohort of children and adolescents (14.9 ± 3.0 years) diagnosed with bipolar disorder (n = 31), other psychotic disorders (n = 29), and other nonpsychotic disorders (n = 30), with no (35.6%) or very little (6.6 ± 9.0 days) previous exposure to antipsychotics. Composite measurements of significant weight gain [weight increase ≥ 5% at three months or increase ≥ 0.5 in body mass index (BMI) z‐score] and ‘risk for adverse health outcome’ (≥ 95^th BMI percentile, or ≥ 85^th BMI percentile plus presence of one other obesity‐related complication) were included. SGAs (risperidone, olanzapine, and quetiapine) were prescribed in comparable proportion among groups. Results: Baseline weight and metabolic indices were not significantly different among diagnoses. Three months after starting treatment with SGAs, more than 70% patients had significant weight gain, BMI z‐score increased in all diagnostic groups (p < 0.001 for all comparisons), total cholesterol increased in the bipolar (p = 0.02) and psychotic (p = 0.01) disorder groups, low‐density lipoprotein cholesterol increased in the bipolar group (p = 0.02), and free T4 decreased in the psychotic disorder group (p = 0.05). More patients with bipolar disorder presented overweight plus ≥ 1 obesity‐related complication at follow‐up. Conclusions: There are early weight gain and metabolic changes across diagnoses in youth treated with SGAs.     

Quetiapine in the treatment of focal tardive dystonia induced by other atypical antipsychotics: a report of 2 cases

The authors report 2 patients with schizophrenia who developed focal tardive dystonia secondary to treatment with atypical antipsychotics (risperidone, olanzapine). When quetiapine was gradually introduced and other antipsychotics were discontinued, these patients experienced remarkable and sustained improvement of their dystonic symptoms, without loss of psychotic symptom control. The mechanism by which quetiapine may improve tardive dystonia caused by other atypical antipsychotics is unclear. Due to its receptor and pharmacologic profile, quetiapine is the atypical antipsychotic that is most similar to clozapine (without its hematologic side effects), which leads the authors to consider it for the treatment of tardive movement disorders.     

Atypical Antipsychotic Use in the Treatment of Psychosis in Primary Care

Atypical antipsychotics are a class of novel agents increasingly employed for the treatment of psychotic disorders. The pharmacodynamic properties of the atypicals appear to impact a broader spectrum of psychotic symptoms than had been appreciated with older generation antipsychotics. In addition, the atypical agents appear to have a reduced risk of neurologic side effects compared with conventional antipsychotic use. Both of these features enhance the appeal of the atypical antipsychotics and may be associated with enhanced patient compliance. The atypical antipsychotics appear to be effective for schizophrenia as well as other psychotic disorders, including schizoaffective disorder and mood disorders with psychotic features. Consequently, atypical antipsychotics are now considered to be the first-line treatment for schizophrenia, with the exception of clozapine, which is considered a second-line agent because of risks associated with its use. This review will discuss the literature on atypical antipsychotic efficacy in psychotic disorders. Issues related to antipsychotic use, dosing, adverse effects, and drug interactions are also discussed.     

Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents

When taking antipsychotic medications, children and adolescents seem to have a higher risk than adults for experiencing adverse events such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects. Side effects may be predicted by the pharmacologic binding profiles of antipsychotics to certain neuroreceptors. Data from 7 recently completed randomized placebo-controlled trials in adolescent schizophrenia and pediatric bipolar disorder that included a total of 1480 patients extend prior results and provide numbers-needed-to-harm as a clinically useful measure of risk. Results from these pediatric studies indicate that adverse effect profiles differ among commonly used antipsychotics. However, more detailed data are needed, as information is lacking regarding carryover or withdrawal effects from prior medications and regarding the masking of effects by adjunctive treatments used to treat agitation, insomnia, or extrapyramidal symptoms and akathisia in these studies. Moreover, randomized head-to-head trials and large-scale studies that investigate predictors of adverse effects as well as the safety and efficacy of interventions aimed at preventing and reversing negative effects of antipsychotics with relevant impact on psychological, psychiatric, and physical functioning are lacking. When choosing an antipsychotic treatment, patients and their families should be included in a careful risk-benefit assessment. Consideration of adverse effects, as well as dietary and lifestyle counseling, should be part of any antipsychotic treatment initiation and continuation. Routine, proactive monitoring of side effects is essential to optimize patient outcomes. In all treatment decisions, the benefits of improving often severe and debilitating manic, psychotic, and aggressive symptomatology must be balanced against the varying risks of adverse effects associated with specific antipsychotic agents in child and adolescent patients.     

A prospective,open-label trial of olanzapine in adolescents with schizophrenia

BACKGROUND: Olanzapine is an atypical antipsychotic that has efficacy in adults with psychotic disorders. This preliminary study examined the effectiveness of olanzapine in adolescents with schizophrenia or its related conditions. METHOD: Adolescents aged 12-17 years (inclusive) with a diagnosis of schizophrenia, schizoaffective, or schizophreniform disorder were enrolled in this 8-week, open-label, outpatient study. The Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), and the Children's Global Assessment Scale (CGAS) were administered as outcome measures. Extrapyramidal side effects were assessed at each visit. Olanzapine was initiated at a dose of 2.5 mg/day and could be increased to a maximum total daily dose of 20 mg. RESULTS: Sixteen participants with a mean age of 13.8 (SD = 1.5) years were treated. Significant improvements were found in the PANSS, CGI severity, and CGAS scores. Reductions in both positive and negative symptoms were found. Increased appetite and sedation were the most frequently reported side effects. Two subjects required treatment for extrapyramidal side effects. CONCLUSIONS: Psychotic symptoms significantly improved during study. Overall, olanzapine was well tolerated. Future studies are needed to confirm these findings, to assess long-term treatment outcomes, and to compare the effectiveness of olanzapine with that of other antipsychotics.     

Olanzapine induces remarkable weight gain in adolescent patients

We present here clinical case reports of three adolescents, aged 14–17 years, who were treated with olanzapine. The daily dose was 10 mg. Prior to olanzapine, the patients were unsuccessfully treated with other antipsychotic drugs. The response to olanzapine for psychotic symptoms was clinically significant in all three patients. The major adverse effect was excessive weight gain. The increases in body mass index (BMI) were 9, 8 and 5 kg/m². One of the patients later lost the additional weight. Especially in adolescents obesity is a serious side effect and potential consequences include numerous health problems. Accepted: 19 February 2001     

The effects of novel antipsychotics on glucose and lipid levels

BACKGROUND: The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels. METHOD: The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses. RESULTS: Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations. CONCLUSION: It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.     

A comparative review of new antipsychotics.

OBJECTIVE: To review the preclinical and clinical properties of various established and putative antipsychotic medications, namely clozapine, risperidone, amisulpride, olanzapine, quetiapine, sertindole, and ziprasidone. METHODS: This paper proposes a decision algorithm for comparing drugs used for psychotic disorders, based on biochemical profile, experimental pharmacology, postiron emission tomography (PET) scan results, and clinical efficacy on positive, negative, anxious, depressive, and cognitive symptoms. This "quotient" aims to compare the different available drugs, regardless of their development and registration status. RESULTS: Antipsychotic drugs have been classified in many ways, mainly according to their chemical structure, clinical effects, receptor affinity, or side effects. Preclinical data have indicated that these drugs might be effective antipsychotic agents, causing fewer extrapyramidal side effects than most of the previously marketed drugs. However, the biological basis for the putative superiority of these drugs in treating psychosis has yet to be ascertained. CONCLUSIONS: Although most antipsychotics have been shown to be at least equivalent to haloperidol on positive symptoms, they must be studied further to establish their absolute and relative efficacy on positive symptoms, negative and primary negative symptoms, cognition, psychotic anxiety, psychotic depression, suicidality, and quality of life. These drugs should be valuable in treating schizophrenia, but their merit in the long-term management of patients with schizophrenia still needs to be confirmed.