Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

Antipsychotic medication has been enormously helpful in the treatment of psychotic symptoms during the past several decades. Unfortunately, several important side effects that can cause significant morbidity and mortality. The two most common are abnormal involuntary movements (tardive dyskinesia) and weight gain progressing through diabetes to metabolic syndrome. A more rare and life-threatening adverse effect is clozapine-induced agranulocytosis (CIA), which has been linked to clozapine use. Clozapine itself has a unique position among antipsychotic medications, representing the treatment of choice in refractory schizophrenia. Unfortunately, the potential risk of agranulocytosis, albeit small, prevents the widespread use of clozapine. Very few genetic determinants have been clearly associated with CIA due to small sample sizes and lack of replication in subsequent studies. The HLA system has been the main hypothesized region of interest in the study of CIA, and several gene variants in this region have been implicated, particularly variants of the HLA-DQB1 locus. A preliminary genome-wide association study has been conducted on a small sample for CIA, and a signal from the HLA region was noted. However, efforts to identify key gene mechanisms that will be useful in predicting antipsychotic side effects in the clinical setting have not been fully successful, and further studies with larger sample sizes are required.     

Differential effectiveness of clozapine for patients nonresponsive to or intolerant of first generation antipsychotic medications

This report examines whether the gains associated with changing to clozapine are greater for people who have been intolerant of first generation antipsychotic medications versus those who have been treatment-nonresponsive to previous agents. We examined data from an open-label, randomized trial that compared clozapine to usual care with first generation agents (n = 227). While most patients (n = 173, 76%) entered that study because they were nonresponsive to at least two first generation antipsychotic medications (treatment nonresponsive [TNR]), 24 percent (n = 54) were eligible because they experienced intolerable side effects (treatment intolerant [TI]). Significantly more TI patients discontinued their clozapine trial during the 2-year study compared to TNR patients, and TI patients taking clozapine were more likely to develop agranulocytosis or severe leukopenia. However, TI patients who remained on clozapine showed significant reductions in problematic behaviors and greater movement toward independent living situations than TNR patients. Clinicians should give serious consideration to offering clozapine and other second generation antipsychotic medications to patients who have demonstrated intolerance to first generation antipsychotic medications.     

Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far?

Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets.     

Agranulocytosis during clozapine therapy

Granulocytopenia and agranulocytosis are considered among the most dangerous adverse effects of clozapine. During the last 15-year period, this atypical antipsychotic agent has been administered to 750 patients managed at the Emergency Psychiatry Services and Clinical Pharmacology Unit of the National Institute of Psychiatry and Neurology (NIPandN; Budapest, Hungary). Granulocytopenia was ascertained in seven, whereas agranulocytosis was diagnosed in two patients of this population. The latter two comprised a 42-year-old female with schizoaffective psychosis and a 35-year-old male with paranoid schizophrenia. The female patient received clozapine in a daily dose of 400 mg, which induced agranulocytosis after 2 months. The male patient was treated with 225-mg/day clozapine and the time to the diagnosis of agranulocytosis was 6 weeks. These adverse reactions were recognized early and the appropriate treatment of agranulocytosis resulted in complete recovery in both cases.     

Switching clozapine responders to olanzapine

BACKGROUND: Clozapine is an atypical antipsychotic indicated for the management of severely ill patients with schizophrenia who have failed to respond adequately to standard drug treatment. The significant risk of agranulocytosis and seizure associated with clozapine has led to the restrictions in its use. Additionally, drug-induced sedation, sialorrhea, enuresis, and weight gain are often cited as problematic consequences of clozapine treatment. Our primary objective was to determine the effectiveness and safety of a method of slow cross-titration from clozapine to olanzapine among patients responsive to clozapine treatment but experiencing medication-induced adverse events. METHOD: Changes in symptomatology, mood, subjective response, and safety were examined in 20 outpatients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder who converted from clozapine to olanzapine. Patients were considered clozapine-responsive as evidenced by improved social function and decreased symptoms with clozapine therapy; however, they were interested in alternative pharmacologic treatment because of clozapine-related side effects. RESULTS: Equivalent efficacy of olanzapine to clozapine was found in 90% of the patients (18/20) in the study group, without rehospitalization or suicidal behavior in any of the patients. Also notable was a reduction in drug-induced side effects and improved subjective response to pharmacotherapy. CONCLUSION: The successful conversion from clozapine to olanzapine has the potential to provide great benefits for the patient, including reducing drug-induced side effects while maintaining symptom control. These preliminary results suggest that further research on converting clozapine responders to olanzapine is warranted.     

Antipsychotic drug action: targets for drug discovery with neurochemical imaging

Schizophrenia is a serious lifelong mental illness for which current treatments may only be partially effective. All antipsychotic medications available at present are thought to exert their main antipsychotic effect through antagonism of dopamine D2 receptors. Clozapine is the most effective antipsychotic drug currently available, but it can cause serious side effects, including agranulocytosis and diabetes. Pharmacologic factors that distinguish clozapine from other antipsychotic drugs have been studied to try to develop safer drugs with similar efficacy to clozapine. These have met with limited success. Neurochemical imaging techniques, such as positron emission tomography, single photon emission tomography and magnetic resonance spectroscopy, have been used to study antipsychotic drug action in living human subjects. These techniques shed a great deal of light on the mechanisms of antipsychotic action and have revealed a number of novel targets for future drug development in schizophrenia. Next-generation antipsychotic medications will aim to improve on the efficacy and tolerability of currently available medications. The authors believe that they are likely to achieve this through drug action at non-D2 sites. Future research and drug development, including the development of medications to prevent progression from the prepsychotic stage to schizophrenia, will rely heavily on neurochemical imaging methods at all stages in the drug-discovery pipeline.     

Prolongation of clozapine-induced leukopenia with olanzapine treatment

Clozapine is a well-known antipsychotic to cause fatal agranulocytosis but there are only a few case reports about the risk of leukopenia and agranulocytosis associated with other atypical antipsychotics. Olanzapine has structural pharmacological similarities to those of clozapine and reports about haematological adverse effects of olanzapine include three groups: the first group includes cases of olanzapine-induced neutropenia, the second informing that olanzapine is safe after clozapine induced agranulocytosis and the third group forms prolongation of clozapine-induced leukopenia with olanzapine use. The aim of this paper is to report a case of prolongation of clozapine-induced leukopenia despite olanzapine treatment and discuss leukopenia caused by atypical antipsychotic use in the light of recent and limited literature.     

Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report.

BACKGROUND: Granulocytopenia and agranulocytosis are severe side effects of clozapine therapy. Even if these side effects are detected early and if clozapine is discontinued, patients suffering from agranulocytosis are extremely endangered by infectious diseases for up to 3 to 4 weeks until hematologic recovery. Therefore, any treatment that reduces this critical time span would decrease the risks of clozapine treatment. METHOD: The case of a patient in whom severe agranulocytosis developed after 7 weeks of clozapine treatment is presented. RESULTS: After clozapine discontinuation, treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein that has been shown to stimulate the proliferation of precursor cells in the bone marrow and their differentiation into granulocytes and macrophages, was initiated. Under GM-CSF treatment, total granulocyte count rose from 63/cu mm to a value greater than 1500/cu mm within 5 days without complications or major side effects. CONCLUSION: This case report suggests that treatment with GM-CSF may lower the risks associated with clozapine-induced agranulocytosis and therefore may indirectly improve the safety of clozapine therapy.     

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia.

Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and serotonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer 'atypical' antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resistant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experience with the newer 'atypical' antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.     

A review of clozapine: an antipsychotic for treatment-resistant schizophrenia

This report reviews over 25 years of literature of the development, pharmacology, proposed mechanism of action, efficacy, adverse effects, and recommendations for use of clozapine. Clozapine, synthesized in 1960, is an efficacious antipsychotic that rarely causes extrapyramidal side effects. However, in the mid-1970s, it was associated with an increased incidence of agranulocytosis resulting in restrictions of use. Recent trials with treatment-resistant schizophrenic patients found clozapine to be superior to chlorpromazine and haloperidol, fortifying the potential contribution of this drug. This has generated optimism that clozapine will obtain Food and Drug Administration approval. Generally well tolerated, the 1% to 2% risk of agranulocytosis can be minimized with careful patient selection, white blood cell (WBC) count monitoring, and weighing of risks versus benefits for use beyond the relatively safe initial 4-week period.     

奥氮平和氯氮平治疗精神分裂症老年患者的对照研究

目的：对比奥氮平与氯氮平治疗精神分裂症老年患者的疗效和安全性。方法：对64例精神分裂症老年患者分别给予奥氮平、氯氮平治疗，其中奥氮平组30例，氯氮平组34例，疗程8周。以阳性症状和阴性症状量表(PANSS)、临床疗效总评量表(CGI)、简明精神病评定量表(BPRS)评定临床疗效。以副反应量表(TESS)和实验室监测评价安全性。结果：治疗结束时，两组PANSS和BPRS总分较治疗前显著降低，组间差异无显著性。两组间从治疗第1周起各时点PANSS减分率差异有显著性。临床有效率：奥氮平组76．7％，氯氮平组64．7％，两组相仿。奥氮平组不良反应较氯氮平组少，常见不良反应为胆碱能作用、嗜睡、体重增加和一过性肝酶升高等。结论：奥氮平治疗精神分裂症的疗效与氯氮平相似，某些不良反应较氯氮平轻而少；是一种安全有效、服用方便的新型抗精神病药。     

Agranulocytosis and granulocytopenia associated with quetiapine.

OBJECTIVE: Quetiapine is a recently introduced atypical antipsychotic. Although adverse effects are mainly mild, more serious infrequent adverse effects including leucopenia are mentioned. METHOD: We describe three case-reports concerning haematological adverse effects of quetiapine. RESULTS: Quetiapine was associated with leucopenia in two patients and clinically apparent agranulocytosis in one patient. CONCLUSION: Although a definite association has not been proven, clinicians should be aware of the possibility of agranulocytosis while using quetiapine. Further post-marketing surveys are required.     

High clozapine concentrations in leukocytes in a patient who developed leukocytopenia

Up to now direct toxic effects or immunological processes have been said to explain clozapine-induced agranulocytosis. However, more recent studies may suggest that not yet metabolized clozapine is taken up by leukocytes and transformed by oxidative processes to apoptosis-inducing metabolites. To verify this hypothesis the concentrations of clozapine were measured in the plasma and the leukocytes of a patient receiving clozapine who developed clozapine-induced leukocytopenia and in 10 patients receiving clozapine who did not show any serious adverse side effects. The patient who developed leukocytopenia showed clozapine concentrations in the leukocytes that were about 8 times higher than the mean clozapine concentrations in the leukocytes in the group of 10 patients receiving clozapine with no changes in the leukocyte count in the history. However, no major difference was found in the clozapine plasma concentrations. The results may suggest that patients at risk of developing clozapine-induced leukocytopenia show increased clozapine concentrations in the leukocytes although the clozapine plasma concentration is in the therapeutic range. It is assumed that changes or abnormalities of clozapine uptake at the cell membrane might play a role in the development of clozapine-induced leukocytopenia and/or agranulocytosis.     

Sexual dysfunction and antipsychotic treatment

Human sexual function is complex and affected in many different ways by schizophrenia and the antipsychotic drugs used in its treatment. The evaluation of the effects of antipsychotics on sexual function in patients with schizophrenia is also complex because the deleterious effects of conventional antipsychotics are superimposed on the effects of the disease itself. Although not extensively researched, sexual dysfunction seems to be frequent in patients with schizophrenia, especially in men. Sexual dysfunction appears, in significant part, to be a direct consequence of dopamine antagonism, combined with indirect effects due to increased serum prolactin concentration. Atypical antipsychotics have a number of potential advantages over standard agents with regard to their impact on sexual function. Clinical reports indicate that atypical antipsychotics are associated with a lower incidence of sexual adverse events than conventional antipsychotics and that there may also be important differences between them in this regard. For example, dose-related increases in prolactin concentrations occur with risperidone whereas olanzapine is associated with mild and transient increases in long-term treatment. Treatment with clozapine does not result in prolactin elevation and, like olanzapine, only transient increases occur with ziprasidone therapy, but the risk of agranulocytosis with clozapine restricts its use. Quetiapine has no more effect on serum prolactin than placebo across its full dose range. Together with its low frequency of reproductive or hormonal side effects and a low incidence of extrapyramidal symptoms, the tolerability profile of quetiapine may be particularly beneficial for many patients. Sexual dysfunction can be an important source of distress to patients and adversely affects compliance, and is one of the factors that must be taken into account when selecting treatment.     

Antipsychotics in bipolar disorders

This article is a review of the various treatments that are currently available, in particular in France, for the treatment of bipolar disorders. This article specifically addresses the use of novel antipsychotic agents as alternative therapy to a lithium therapy and/or the use of conventional antipsychotics. The prevalence of bipolar disorder over a lifetime is around 1% of the general population. Bipolar disorder consists of alternating depressive and manic episodes. It mainly affects younger subjects, and is often associated with alcohol and drug addictions. There are two main subtypes of bipolar disorder. According to the DSM IV-R, type 1 of bipolar disorder is characterised when at least one manic episode (or a mixed episode) has been diagnosed. Type 2 of bipolar disorder is related to patients enduring recurrent depressive episodes but no manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the bipolar disorder. Lithium therapy has been effectively and acutely used for patients with pure or elated mania and its prophylaxis. However, lithium medication may worsen depressive symptoms when used for a long term maintenance therapy. Additionally, mixed mania, rapid cycling type patients and bipolar disorder associated with substance abuse do not respond well to lithium therapy. In addition to the lithium therapy or in place of a lithium therapy, one can report the frequent use of antipsychotic agents in respect of patients with bipolar disorder during both the acute and maintenance phases of treatment. Antipsychotic agents have been used for almost forty years and may be used in combination with a lithium therapy. Conventional antipsychotics are effective but they may induce late dyskinesia, weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where antipsychotic agents are combined with a lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to lithium therapy. As such, valproate has received regulatory approval for the acute treatment of mania and carbamazepine has been indicated for this condition in a number of countries. Divalproex (Depakote) has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants (lamotrigine, gabapentin and topiramate) are currently being tested. Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate. They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication. There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics. Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled. Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death. In addition, clozapine has been shown to produce significant weight gain and sialorrhea as well as significant anticholinergic effects. As a result, clozapine should not be prescribed in the first place. As opposed to clozapine, there are open-label reports and controlled studies in respect of risperidone and olanzapine. Two recent double-blind studies of acute mania found olanzapine to be more effective than placebo. Based on these two studies, olanzapine has recently been approved for the indication of mania. The effects of olanzapine and divalproex in the treatment of mania have also been compared in a large randomized clinical trial. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more weight gain and cases of dry mouth, increased appetite and somnolence were reported with olanzapine while more cases of nausea were reported with divalproex. The comparison of olanzapine with lithium for the treatment of mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that olanzapine may have specific prophylactic mood-stabilizing properties. Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and antidepressant effects. Systematic trials have shown that risperidone may be effective and safe in the treatment of acute mania, as an add-on therapy with lithium or valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study, risperidone seems to be effective and safe as long-term adjunctive therapy in treatment-resistant bipolar and schizo-affective disorders, with no exacerbation of manic symptoms. Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and weight gain. A naturalistic comparison of clozapine, risperidone and olanzapine in the treatment of bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. However, this may partially be caused by the use of mood-stabilizing agents. Bipolar and schizo-affective patients now require combination therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-stabilizing agents with conventional antipsychotics and atypical antipsychotics. Combination therapies produce a number of adverse side effects. Atypical antipsychotics (other than clozapine) are now rated as first-line agents for adjunctive treatment of mania because they produce less adverse side effects. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an antipsychotic is required for long-term maintenance.     

Effects of antipsychotic drugs on cytokine networks

It has been known since the 1950s that phenothiazines have immunomodulatory effects. This review summarizes recent evidence suggesting that antipsychotic drugs, in particular chlorpromazine and the atypical compound clozapine, influence the production of cytokines. Cytokines, organized in networks of related peptides with pleiotropic functions, are pivotal humoral mediators of infection and inflammation, and they play an important role in hematopoiesis and autoimmunity. Therefore, the effects of antipsychotic drugs on cytokine networks are important for the understanding of immune-mediated side effects of these drugs, e.g. agranulocytosis. In addition, modulation of cytokine production by antipsychotic agents suggests that these drugs might be useful for the treatment of diseases which primarily involve the immune system. Moreover, because cytokines are known to have numerous effects on the CNS, they may mediate effects of antipsychotic drugs on brain functions. Finally, the influence of antipsychotic drugs on cytokine networks is an important confounding factor in studies investigating disease-related immunopathology in psychiatric disorders. This review provides a synopsis of the data published on these topics and outlines future research perspectives.     

Reversible neutropenia during treatment with olanzapine: three case reports.

Olanzapine is an atypical antipsychotic with a low incidence of extrapyramidal-motoric side effects. Its chemical structure is related to clozapine, which is known to induce neutropenia in up to 3% and agranulocytosis in approximately 1% of patients. It has been discussed controversially whether olanzapine also has a potential to induce neutropenia and agranulocytosis. Up to now, seven case reports of haematopoetic disturbances during olanzapine treatment have been published, including one case of olanzapine-induced agranulocytosis (Naumann et al. 1999), two cases of neutropenia (Steinwachs et al. 1999) and one leucopenia (Meissner et al. 1999). We report three subjects with reversible neutropenia under olanzapine, with rapid normalisation of neutrophil cell counts after discontinuation of olanzapine. In one case neutropenia occurred after administration of a single dose of olanzapine, in another case after 6 weeks of treatment. In both cases, patients had no clinical complications. In the third case, neutropenia appeared after 1.5 years of treatment followed by development of pneumonia. Two cases were recorded within the German drug surveillance project (AMSP); the third case was observed in a randomised, double-blind, multicentre study comparing olanzapine with clozapine.     

Myotoxicity in acute clozapine overdose

Clozapine, an atypical antipsychotic has been associated with several side effects like sialorrhoea, sedation, tachycardia, agranulocytosis and seizure. Myotoxicity and neurotoxicity have also been reported with long-term use of clozapine. We report here a case of myotoxicity developing after acute overdose of clozapine. A 17-year-old daughter of a schizophrenic father consumed 3.9 g of clozapine in an attempted suicide. Clinical features of myotoxicity were detected on the third day, after the patient regained full consciousness. Elevated creatinine phosphokinase and muscle biopsy confirmed myositis. The patient also had tachycardia, which persisted for 10 days. This combination of myositis-induced muscle weakness and tachycardia is likely to be associated with poor outcome in clozapine overdose.