Clozapine/olanzapine-induced recurrence or deterioration of binge eating-related eating disorders

Summary Objective. To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs). Method. Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment. Results. Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [χ² = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3–725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine. Conclusion. Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.     

Health care costs of therapy-refractory schizophrenic patients treated with clozapine: a study in a community psychiatric service in Italy

This study evaluates the utilization of clozapine in the treatment of therapy-refractory schizophrenia in terms both of patterns of care and of health care costs in a community psychiatric service in Italy. Data covering the year prior to commencing clozapine and the year following the initiation of the therapy were collected. Clinical outcome was assessed by means of the Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) scales. Cost analysis followed a two-step procedure: (i) to record all health care services provided to patients and (ii) to assign a monetary value to each service. Three of the 15 patients enrolled in the study dropped out before the end of the 12-month period of therapy. Considering the 12 patients on clozapine treatment for at least 1 year, clinical improvements are associated with a substantial modification of the pattern of care. While patients in the pre-clozapine period were mainly managed in hospital settings, patients on clozapine were prevalently placed in the community and participated in intensive rehabilitative programmes. The higher costs of drug therapy and community services in the post-clozapine period were more than offset by the lower costs of acute hospital care.     

Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior

BACKGROUND: Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome. METHOD: In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001. RESULTS: Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings. CONCLUSION: The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.     

Atypical antipsychotics and suicide in mood and anxiety disorders

Abstract:  Globally, a million people commit suicide every year, and 10–20 million attempt it. Mood disorders, especially major depressive disorder (MDD) and bipolar disorder, are the most common psychiatric conditions associated with suicide. Primary (psychiatric and physical illness), secondary (psychosocial), and tertiary (demographic) risk factors for suicide have been identified. Comorbid psychiatric illness, particularly anxiety symptoms or disorders, significantly increase the risk of suicidal behavior. Current standard risk assessments and precautions may be of limited value, while assessing the severity of anxiety and agitation may be more effective in identifying patients at risk. Lithium is the medication that has most consistently demonstrated an antisuicidal effect. The effects of antidepressants and conventional antipsychotics on suicide risk are uncertain, but atypical antipsychotics appear promising. Atypical antipsychotics have beneficial effects on depressed mood both in patients with MDD and in patients with bipolar disorder. In addition, data in patients with schizophrenia have demonstrated a significant improvement in the incidence of suicidal behavior with clozapine compared with olanzapine. Electroconvulsive therapy appears to have an acute benefit on suicidality.     

Psychopharmacologic strategies for the prevention of suicidal behavior in bipolar patients

Current pharmacological strategies for the prevention of the suicide behavior in bipolar patients are reviewed. Additionally, these studies are discussed in the context of a stress–diathesis model, to explore whether this model explains the empirical fact that some drugs appear to have antisuicidal properties while others do not. A review of the relevant literature suggests that lithium and serotonin enhancing antidepressants reduce suicidal behavior in bipolar patients. A stress–diathesis model explains the differential effect of such medications compared to other antidepressants or mood stabilizers by proposing additional effects of these medications on the diathesis for suicidal behavior. This effect may be mediated by augmentation of serotonergic function, which is linked to suicidal behavior. Serotonergic enhancing drugs therefore can potentially reduce suicidal behavior.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT)

BACKGROUND: Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients. METHODS: A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of "much worsening of suicidality" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved. RESULTS: Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P =.03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P =.03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P =.01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P =.01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P =.73). CONCLUSIONS: Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.     

Clozapine: its impact on aggressive behavior among patients in a state psychiatric hospital.

Clozapine has shown consistent efficacy against positive symptoms of psychoses, and emerging reports indicate improvements in aggression and suicidality. This study evaluated the impact of clozapine aggression in a psychiatric hospital. Over a three year period, 137 subjects with schizophrenia or schizoaffective disorder received clozapine, of whom nearly 50% (n=69) experienced seclusion or restraint. Using a mirror-image study design, seclusion and restraint rates were computed per patient-month pre-clozapine and compared during clozapine treatment to a maximum of 12 months in either direction. The rest of the hospital not receiving clozapine served as a comparator group. Statistically significant reductions occurred in both seclusion (0.44+/-0.46 vs. 0.16+/-0.32, z=-3.91, p=0.0003) and restraint (0.34+/-0.47 vs. 0.08+/-0.23, z=-2.27, p=0.032) during clozapine treatment as compared with the pre-clozapine period. The comparator group experienced a low rate of seclusion and restraint throughout. While there are limitations to a mirror-image design, this study supports the emerging data on the benefits of clozapine for aggressive and violent patients with psychoses. Preliminary data suggests other second generation antipsychotic agents may have similar effects.     

Antisuicide properties of psychotropic drugs: a critical review

The authors consider the extent to which psychotropic medications demonstrate benefits in the prevention of suicidal behavior in psychiatric patients. Results of a MedLine search are critically reviewed for lithium, divalproex and other anticonvulsants, conventional and atypical antipsychotics, and antidepressants. The existing literature is almost entirely limited to noncontrolled, often retrospective studies that do not control for potential biases in treatment selection, the use of multiple medications, the impact of medication nonadherence, and nonrandomized treatment discontinuations. Nevertheless, an extensive literature has arisen regarding observed reductions in suicidal behavior with lithium for mood disorders and, to a lesser extent, with clozapine for schizophrenia. A substantially smaller literature suggests more negative than positive data with divalproex or carbamazepine in bipolar disorder, while minimal information exists regarding suicidality with atypical antipsychotics other than clozapine. Studies of antidepressants have mostly been short-term and have focused more on whether they induce (rather than ameliorate) suicidal thoughts or behaviors. The sum of existing studies is generally inconclusive about whether antidepressants appreciably reduce risk for suicide completions. Relatively little is known about pharmacotherapy effects on suicidal ideation as distinct from behaviors. Possible mechanistic considerations for understanding antisuicide properties include a therapeutic impact on depression, impulsivity, or aggression, potentially mediated through serotonergic or other neuromodulatory systems. Recommendations are provided to guide future research as well as clinical practice.     

Comparative efficacy of risperidone and clozapine in the treatment of patients with refractory schizophrenia or schizoaffective disorder: a retrospective analysis

BACKGROUND: Clozapine is effective in up to 60% of patients with refractory schizophrenia, whereas the efficacy of risperidone remains unknown. This retrospective study examined the relative efficacy of these drugs in chronically institutionalized patients refractory to conventional antipsychotic agents. METHOD: A total of 24 patients who at different time periods had received adequate trials of both clozapine and risperidone and met our inclusion criteria for minimum dose and duration of each trial were included; for clozapine, a minimum dose of 300 mg/day had to be maintained for at least 12 weeks, and for risperidone, a minimum dose of 6 mg/day for at least 6 weeks. Information obtained from systematic retrospective chart review was blindly rated by 2 psychiatrists using the 7-point Clinical Global Impressions-Improvement (CGI-I) scale on overall clinical state and along specific symptom domains of positive symptoms, negative symptoms, and aggressive behavior. RESULTS: The mean +/- SD dose was 520+/-94 mg/day for clozapine and 7.5+/-2.2 mg/day for risperidone. Fourteen patients (58%) were classified as responders to clozapine, while 6 (25%) responded to risperidone (CGI-I score of 1 or 2); on specific symptom domains, response rates to clozapine were 38% (9/24) on positive symptoms, 29% (7/24) on negative symptoms, and 71% (12/17) on aggressive behavior. For risperidone, response rates were 17% (4/24) on positive symptoms, 8% (2/24) on negative symptoms, and 41% (7/17) on aggressive behavior. CONCLUSION: The results of this study support the utility of first giving a risperidone trial in a treatment algorithm for refractory patients because of its better risk/benefit profile compared with clozapine. Clozapine, however, remains our gold standard in the management of these patients.     

Platelet serotonin concentration and suicidal behavior in combat related posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a serious and global problem, a psychiatric disorder that frequently occurs with different comorbidities, and is associated with a high suicide rate. Pathophysiologically, both PTSD and suicidal behavior are related to disturbances in the central serotonergic system. Serotonin (5-hydroxytryptamine, 5-HT) controls emotional behavior, anxiety, impulsivity and aggression, and nearly all known antidepressants and antianxiety drugs affect 5-HT transmission. Platelet 5-HT can be used as a limited peripheral marker of the central serotonergic synaptosomes, since it is related to particular basic psychopathological characteristics of several psychiatric disorders. Platelet 5-HT concentration has been reported to be similar in PTSD subjects and healthy controls, but suicidal patients across different psychiatric diagnoses have reduced platelet 5-HT concentration. This study examined platelet 5-HT concentration by the spectrofluorimetric method in male subjects: 73 suicidal and 47 non-suicidal veterans with current and chronic combat related PTSD, 45 suicidal and 30 non-suicidal comparative non-PTSD subjects and 147 healthy men. The presence of suicidal behavior (score=0, non-suicidal; scores > or =1, suicidal) was assessed with the Hamilton Depression Rating Scale-17 (HDRS). Platelet 5-HT concentration was significantly lower in suicidal PTSD and non-PTSD patients compared to non-suicidal patients or healthy controls. Since the majority of patients scored very low on item 3 of HDRS, no significant correlation between suicidal scores and platelet 5-HT concentration was found. These results show that reduced platelet 5-HT concentration is related to suicidal behavior in PTSD, and suggest that platelet 5-HT concentration might be used as a peripheral marker to predict suicidal behavior across psychiatric diagnoses.     

Is clozapine antisuicidal?

Suicide accounts for approximately 10% of patient deaths in schizophrenia. The atypical antipsychotic clozapine (Clozaril), successful in treatment-resistant patients with schizophrenia, may have an additional antisuicidal effect. Numerous published reports, including the collaborative International Suicide Prevention Trial, have compared mortality rates between clozapine recipients and patients receiving other forms of antipsychotic treatment and observed a significant reduction in patient risk for suicide with clozapine therapy. Preliminary reports indicate improvements in suicidality in schizophrenia patients treated with other modern atypical antipsychotics, for example olanzapine [Zyprexa], risperidone [Risperdal] and sertindole [Serdolect], but further investigation is required to clarify their role as antisuicidal drugs. It has been estimated that 53 suicides in treatment-resistant patients could have been prevented by clozapine, but the number of lives saved may be significantly higher if clozapine therapy was extended to treatment responders at a high risk for suicide.     

Psychopharmaka zur Behandlung suizidaler Patienten und zur Suizidprävention

Suicidality represents a frequent phenomenon in affective and psychotic disorders but the treatment of acute and chronic suicidality is still a controversial issue. Especially the efficacy of antidepressant and neuroleptic drugs for prevention of suicide continues to be debated. There is a lack of evidence due to limitations of methodological studies and ethical concerns are a major issue. Considering methodological problems in the conducted studies the often insufficiently valued differentiation between suicidal thoughts and actual suicidal behavior has to be emphasized. With the exception of lithium and clozapine suicide-preventing effects of antidepressants and neuroleptics could not yet be demonstrated. Regarding new antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) even the possible new onset of suicidal thoughts and ideations as an adverse effect needs to be stressed. Considering the frequent occurrence of suicidality the currently available evidence is undoubtedly insufficient. The improvement of study concepts and especially a more differentiated consideration of the vague term “suicidality” seems to be essential. An underrepresentation of the evidence-based therapeutic options with lithium and clozapine in the treatment of suicidal patients needs to be avoided.     

Ecological studies of antidepressant treatment and suicidal risks

Ongoing discussion of potential benefits and risks of antidepressant treatment with respect to suicidal behaviors includes many ecological, or population-based, correlational studies of temporal or regional trends in suicide rates and rates of usage of modern antidepressants including serotonin-reuptake inhibitors (SRIs). Since this body of research has not been compiled and evaluated, we used computerized literature searching to identify 19 relevant published studies. They yielded heterogeneous findings: only 8/19 found significant inverse correlations between rising sales of modern antidepressants in the 1990 s and falling suicide rates not anticipated in the 1980s. Average reductions in suicide rates in the 1990 s (10.7%) and 1980s (10.0%) differed little in 11 studies with data from both eras. Reduction of suicide rates in the 1990 s was unrelated to geographic region, population size, units of analysis, publication year, or growth in antidepressant usage, but was greater with higher initial suicide rates, in men, and in older persons. In the same decade, suicides rates decreased in only half of 79 large countries. Overall, these findings yield limited and inconsistent support for the hypothesis that increased use of modern antidepressants might limit suicide risk, and no evidence that the risk increased. Suicidal risk is determined by complex factors, including access to clinical services, in general, and more comprehensive treatment of depression, in particular. Overall, as with findings from randomized trials and cohort or case-control studies, evidence of specific antisuicidal effects of antidepressant treatment from ecological analyses remains elusive.     

Suicidality and fluoxetine: is there a relationship?

A recent report of six depressed patients who developed intense, violent suicidal preoccupation after 2 to 7 weeks of fluoxetine treatment prompted the authors to survey 27 psychiatrists who treated 1017 depressed outpatient with antidepressants during 1989: 3.5% (8/231) of those treated with fluoxetine alone, 6.5% (4/62) of those treated with fluoxetine and tricyclics, 1.3% (5/385) of those treated with tricyclics alone or with lithium, and 3.0% (3/101) of those treated with other antidepressants became suicidal only after treatment with these antidepressants was initiated. None of these patients, however, reported intense suicidal thoughts of the degree described in the previously reported six cases. The difference in incidence of suicidal ideation occurring only after initiation of treatment was not significant between patients treated with fluoxetine alone and those receiving the other antidepressant treatments.     

The suicidal process in suicides among young people

Runeson BS, Beskow J, Waern M. The suicidal process in suicides among young people. Acta Psychiatr Scand 1996: 93: 35–42. © Munksgaard 1996. Fifty-eight consecutive suicides among 15– to 29-year-olds (42 men and 16 women) were investigated by modified psychological autopsies and examined from the perspective of the suicidal process. Previous suicide attempts were evident in 66% and more than two suicide attempts found in 17% of men and in 56% of women. The median interval from first suicidal communication to the suicide was shorter in men than in women (12 vs 42 months). The median interval was 47 months in schizophrenia, 30 months in borderline personality disorder, 3 months in major depression and < 1 month in adjustment disorder. There were also differences in the prevalence of next-of kin models for suicidal behavior, previous suicidal communication and in the characteristics of the suicide. We conclude that focusing on the process heightens understanding of serious suicidal behavior in young people.     

Aripiprazole improves olanzapine-associated obsessive compulsive symptoms in schizophrenia

Many schizophrenic patients have comorbid obsessive-compulsive syndromes (OCS) frequently associated with antiserotonergic second-generation antipsychotics such as clozapine and olanzapine. Whereas cognitive behavioral therapy and antiobsessive antidepressants brought up inconsistent results, pharmacological add-on strategies were able to alleviate OCS. One suggestive agent for antiobsessive add-on treatment is aripiprazole, a partial agonist at dopamine and serotonin receptors. Here, we summarize the course of a patient with paranoid schizophrenia. She developed OCS during long-term treatment with olanzapine at 20 mg/d over a period of 10 years. Baseline assessment showed severe obsessions (Yale Brown Obsessive Compulsive Scale (YBOCS) subscale score : 13) and compulsions (YBOCS subscale score : 10), whereas the psychotic syndrome was compensated (Positive and Negative Syndrome Scale, 11/17/28). The combination with aripiprazole (15 mg/) over a period of 12 weeks resulted in a marked improvement of OCS (YBOCS, 8/3) and some further improvement of the psychotic symptoms (Positive and Negative Syndrome Scale, 9/13/27). This observation points toward an antiobsessive potency of aripiprazole in combination with olanzapine, quite similar to approaches involving clozapine. Hence, the proposed strategy should be further evaluated in prospective controlled trials.     

Suicidal behavior-advances in clinical and neurobiological research and improvement of prevention strategies

Suicide is the 14^th leading cause of death worldwide. It is responsible for 1%-5% of all mortality. This article highlights the latest developments in universal, selective, and indicated prevention strategies. Concerning universal suicide prevention, current research has shown that strategies such as restricting access to lethal means (e.g., control of analgesics and hot-spots for suicide by jumping) and school-based awareness programs are most efficacious. Regarding selective prevention, substantial progress can be expected in psychological screening methods for suicidal behavior. The measurement of implicit cognition proved to be more valid in predicting future suicide attempts than classic clinical assessment. Latest developments are smartphone-based interventions and real-time monitoring of suicidal behavior. Great effort has been made to establish valid neurobiological screening methods (e.g., genetic and epigenetic risk factors for suicide, hypothalamic-pituitary-adrenal axis) without yielding a major bre-akthrough. Potentially, multiple biomarkers rather than a single one are necessary to identify individuals at risk. With regard to indicated prevention in form of psychopharmacological treatment, recent pharmacoepidemiological studies and meta-analyses have supported a protective role of antidepressants, lithium, and clozapine. However, the data concerning a specific anti-suicidal effect of these drugs are currently not consistent. Promising results exist for ketamine in reducing suicidal ideation, independently of its antidepressant effect. Concerning psychotherapy, recent findings suggest that psychotherapeutic interventions specifically designed to prevent suicide re-attempts are most efficacious. Specifically, cognitive behavioral therapy and psychodynamic therapy approaches proved to decrease the number of suicide re-attempts significantly.