Introduction Of Clozapine Research Articles

Changes in psychopharmacotherapy for patients with schizophrenia in a psychiatric institution in Japan: A 12-year prescription survey pre- and post-introduction of clozapine

Psychopharmacotherapy for patients with schizophrenia in Japan has a long history of polypharmacy, which is rare worldwide but remains a critical problem. One reason for this is that clozapine was not available in Japan until 2009. We aimed to investigate the changes in psychopharmacotherapy in patients with schizophrenia over 12 years pre- and post-introduction of clozapine to clarify how psychopharmacotherapy for patients with schizophrenia has changed with the introduction of clozapine. We retrospectively collected data from the medical records of inpatients diagnosed with schizophrenia at the Okayama Psychiatric Medical Center. Chlorpromazine equivalent (CP-eq) decreased from 1276.6 mg/day in 2009 to 613.9 mg/day in 2020. The prescribed daily dose/defined daily dose (PDD/DDD) decreased from 3.0 in 2009 to 1.2 in 2020. The monotherapy rate increased from 24.4 % in 2009 to 74.6 % in 2020. Our institution began using clozapine in 2010, and the prescription rate for clozapine increased to 37.3 % in 2020. The prescription rate for more than three antipsychotics decreased from 27.8 % in 2009 to 0.8 % in 2020.The increase in clozapine prescription has contributed to an increased rate of antipsychotic monotherapy and a decreased rate of polypharmacy, promoting the optimization of schizophrenia medication. Clozapine therapy should be further promoted in Japan to reduce treatment-resistant schizophrenia due to polypharmacy as much as possible.

The introduction of clozapine at the Nathan Kline Institute in New York and its long-term consequences

Nathan S. Kline was a pioneer in psychopharmacology in the United States (US). In 1952, Kline started a research unit at Rockland State Hospital, New York. Kline brought clozapine from Switzerland since it was not yet available in the US. At Rockland State Hospital, George Simpson had conducted antipsychotic trials and had developed scales to assess movement disorders. In 1974, Simpson published the first US clozapine trial. In 1978, he published on 1) the effect of clozapine on tardive dyskinesia and 2) high plasma clozapine concentrations in two patients with seizures. His experience of clozapine withdrawal symptoms in his first 2 trials led in the future to more articles in this area. In Philadelphia, Simpson designed a double-blind randomized clinical trial (RCT) with 3 doses (100, 300 and 600 mg/day) which was published in 1999. From the 50 patients started on the RCT, 47 provided repeated plasma clozapine concentrations every other week of the RCT. This rich database of plasma clozapine concentrations under controlled conditions has contributed to many of the advances in clozapine pharmacokinetics in the last 5 years including: 1) obesity can be associated with clozapine poor metabolism (PM) status, 2) a clozapine ultrarapid metabolizer (UM) with a minimum therapeutic dose of 1591 mg/day, 3) a case of clozapine intoxication dropped from the RCT due to pneumonia, 4) cases of increased plasma concentrations during clozapine-induced fever, 5) the possibility that African-Americans may need higher clozapine doses than those of European ancestry, and 6) three indices of non-adherence.

Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring: Can the regulations be relaxed?

After the introduction of clozapine eight Finnish patients died after developing agranulocytosis. Clozapine was withdrawn from the market and only reintroduced with strict mandatory white blood cell monitoring as long as treatment lasts and thresholds at which clozapine must be discontinued definitively. The fear of agranulocytosis and the need for intensive blood monitoring is the single most important barrier for prescribers and patients alike and leads to underprescription of the only effective and approved medication for treatment-resistant schizophrenia. We summarize evidence that the risk of agranulocytosis is smaller than perceived at the time of reintroduction, is concentrated in the first 18 weeks of treatment, is not greater than with other antipsychotics thereafter and that frequent blood monitoring has not demonstrably decreased the rate of agranulocytosis. Therefore we propose 1) mandatory monitoring of the absolute neutrophil count (ANC) exclusively during the first 18 weeks of clozapine treatment, 2) that thereafter the prescriber and the well-informed patient decide together about further monitoring frequency, 3) that clozapine treatment must be stopped if the ANC falls below 1.0 × 109/L. Continuation of clozapine or a rechallenge are possible if prescriber and patient determine that the benefits outweigh the risks. 4) National registries which control the haematologic monitoring are unnecessary and do not help to reduce clozapine-induced agranulocytosis. They should at least be restricted to the first 18 weeks of clozapine use.

Persistent delusional disorder: psychopathological remission associated with clozapine-induced epileptic seizures

IntroductionPersistent delusional disorder has some features similar to schizophrenia, although the functionality of patients with this diagnosis is usually higher and is diagnosed at an older age. Although the pharmacological treatment of schizophrenia has been studied extensively, there is not much data on the treatment of persistent delusional disorder. Regarding the use of clozapines specifically in persistent delusional disorders, there are some case reports with encouraging results. Electroconvulsive therapy is not generally used as a treatment for persistent delusional disorder.ObjectivesTo reflect on the relevance of using electronvulsive therapy in the treatment of persistent delusional disorder.MethodsThrough the description of a clinical case in which there was evidence of remission of resistant psychotic symptoms after clozapine-induced epileptic seizures, the authors hypothesize the existence of a direct relationship between the crisis and the resolution of a persistent delusional disorder.ResultsA.F., 78 years old, male. No personal history of psychiatric or medical-surgical illness. Admitted for psychotic decompensation framed in persistent delusional disorder. The patient underwent pharmacological treatment with resistance to three lines of antipsychotics. With the introduction of clozapine 100mg/day, the patient had two epileptic seizures, followed by complete remission of psychotic symptoms.ConclusionsThe clinical case described refers to a patient diagnosed with resistant persistent delusional disorder, with almost immediate resolution of the condition after epileptic seizures induced by clozapine. Taking into account the clinical response in our patient to two spontaneous epileptic seizures, we hypothesize that electroconvulsive therapy may be effective in the treatment of persistent delusional disorder.Disclosure of InterestNone Declared

Neutropenia induced by several second-generation antipsychotics :A case report

IntroductionAntipsychotic medications remain the mainstay of the treatment of various psychiatric disorders, particularly schizophrenia. However, this therapeutic class can induce a range of side effects. Although the treatment with second generation antipsychotics includes a lower risk for extrapyramidal symptoms as compared to first generation antipsychotics, there are numerous adverse events that can result from atypical antipsychotics. Since the introduction of clozapine, there has been increased awareness regarding antipsychotic-induced hematological side effects.ObjectivesThe objective of this case report is to highlight the importance of the management of antipsychotic-induced neutropenia.MethodsWe report a patient with history of schizophrenia who developed neutropenia induced by Haloperidol, Chlorpromazine, Olanzapine, Amisulpride and Aripiprazole.ResultsWe present a case of a 43-year-old male patient with a history of schizophrenia, admitted in our department for the management of a state of agitation in the context of a relapse of his condition. On admission, the patient experienced psychotic symptoms, including delusions and auditory hallucinations, in addition to negative symptoms, such as affective flattening, alogia, avolition and asociality. He was then started on 12 mg of Haloperidol and 200 mg of Chlorpromazine with a white blood cells count (WBC) of 5.98 x 109/L and absolute neutrophil count (ANC) of 2.52 x 109/L (WBC reference range: 4.0-10.0 x 109 /L; ANC reference range: 1.5-7.0 x 109 /L). The patient did not report adverse events on this medication.15 days into hospitalization, a mild neutropenia was detected (WBC=3.92 x 109 /L and ANC=1.01 x 109 /L), leading to a discontinuation of the antipsychotic treatment. No signs of infection were found. After one month, the patient had a normal WBC and ANC. Aripiprazole was discussed as a first alternative and was begun at 5 mg/day and then at 10 mg/day. After one week of treatment with Aripiprazole, the patient’s WBC was normal, but the ANC decreased again leading to a moderate neutropenia (ANC=0.91x 109 /L). The antipsychotic treatment was once again discontinued and the hematological evaluation found no other identifiable cause. Afterwards, neither Olanzapine nor Amisulpride showed significant response to this adverse effect. Finally, the administration of Risperidone led to a positive outcome on the WBC and the ANC.ConclusionsAwareness regarding the hematological side effects of antipsychotics should increase and clinical management of this type of adverse event should be a subject of interest among psychiatrists.Disclosure of InterestNone Declared

Dopamine supersensitivity psychosis and delay of clozapine treatment in patients with treatment-resistant schizophrenia.

Both the underutilization of clozapine and treatment resistance of patients to clozapine are serious problems worldwide. Identifying clinical markers predicting response to clozapine would help clinicians more effectively utilize clozapine treatment. The present study retrospectively assessed dopamine supersensitivity psychosis (DSP) in addition to other measures such as age at disease onset and delay of clozapine introduction for a total of 47 treatment-resistant schizophrenia (TRS) patients. The response to clozapine was judged with CGI-C at 1 and 2 years from clozapine introduction. Results revealed that the DSP group tended to have a longer delay between designation of TRS and introduction of clozapine and continued to have slightly more severe psychopathology after treatment with clozapine, showing only slight improvement. The logistic regression analysis showed that the age at disease onset was the only significant indicator, predicting responsiveness to clozapine: patients with an onset age <20 years had a significantly better response to clozapine than patients with an onset age ≥20 years. The present study suggests that DSP might be related to a longer delay in clozapine introduction and the persistence of refractory symptoms despite clozapine treatment, whereas early age of disease onset might be related to a better response to clozapine.

Clozapine induced pneumonia: A case report of diagnostic difficulties in the time of Covid-19

IntroductionClozapine is a drug that can cause several side effects. Among the less commonly described is a drug-induced lung disease. Due to its non-specific clinical presentation, it represents a diagnostic challenge. The diagnosis is made based on: 1. Association of exposure to the agent and development of symptoms, 2. Pulmonary infiltration, 3. Exclusion of other causes, 4. Withdrawal of symptoms when the agent is excluded from therapy. To date, there have been only a few descriptions of this condition.ObjectivesCase report of rare side effect of clozapine.MethodsCase reportResultsCase report: male patient (37) with schizophrenia, was hospitalized after a brutal suicide attempt. The PCR test for COVID-19 that was routinely performed on admission was negative. After the introduction of clozapine into therapy, the patient became febrile. There was a drop in oxygen saturation, a Lung CT scan showed inflammatory changes („ground-glass opacities“), and COVID-19 pneumonia was suspected. Due to the worsening of the mental state, the dose of clozapine was increased. The physical condition further deteriorated: febrile, sO2 declining. After repeated PCR tests for COVID-19 (all negative), interstitial pneumonia caused by clozapine was suspected, and clozapine was excluded from therapy. The physical condition started to improve. Quetiapine was introduced, and occasional episodes of agitation were relieved with intramuscular diazepam. In the following days, the patient’s mental state improved and he was discharged.ConclusionsDespite its superiority over other antipsychotics, clozapine was with good rationale ranked third in treatment guidelines for schizophrenia.DisclosureNo significant relationships.

M204. ULTRA-RESISTANT SCHIZOPHRENIA IS ASSOCIATED WITH A DELAY TO INITIATE CLOZAPINE AND WITH LESS ABDOMINAL OBESITY. SEX DIFFERENCES IN INSULINEMIA AND LEPTIN LEVELS ARE OBSERVED BETWEEN RESPONDERS AND NOT RESPONDERS

Background30% patients suffering from schizophrenia fail to obtain therapeutic benefit even after two appropriate antipsychotic trials and are considered resistant. The recommended treatment in these cases is clozapine (CLZ), but only 40% of patients with resistant schizophrenia show clinical response, a condition called ultra-resistance (UR) and defined as the lack of antipsychotic response after 8 to 12 weeks of treatment with at least 400 mg/day of clozapine or plasma levels ≥ 350 ng/ml. The objective of the present study is to identify factors associated with UR in in a group of patients from Argentina.MethodsA paired case-control study was conducted, being cases those patients with UR schizophrenia and controls those who responded to CLZ; both groups were matched by age and sex. The response to CLZ was measured using the PANSS (UR was defined with a total score ≥ 80). The following parameters were compared between groups: months of untreated psychosis, months until the introduction of clozapine, body mass index (BMI), waist circumference, fasting blood glucose, insulinemia, triglyceridemia, HDL cholesterol, ultrasensitive C-reactive protein (CRP) and plasma leptin levels. Clozapine and nor-clozapine plasma trough levels were measured by HPLC-MS/MS.Results9 men (M) and 7 women (W) with the diagnosis of UR schizophrenia were matched with the same number of responders (R) to clozapine. Total PANSS scores (mean ± SD) for each group were as follows: W-R 48.9 ± 11; W-UR 88.4 ± 6 (p < 0.0001); M-R 60.5 ± 7; M-UR 112.8 ± 23 (p < 0.0001). CLZ dose was significantly higher both in W-UR and in M-UR than in paired controls (p < 0.05). Nonsignificant differences were observed for nor-CLZ plasma concentration among groups. Clozapinemia was not different among men but it was significantly higher in W-UR in comparison with W-R (p < 0.05).Significant differences were detected in the amount of months that passed before initiation of CLZ both for women (W-R 140.9 ± 124, W-UR 255.6 ± 153, p < 0.005) and men (M-R 104.0 ± 51. 6 versus M-UR 174.6± 65; p < 0.05). Body mass index (kg/m2) was significantly lower in UR patients: W-R 35.3 ± 6 versus W-UR 26.9 ± 3 (p < 0.05) and M-R 30.6 ± 5 versus M-UR 22.7 ± 4 (p <.005). Waist circumference (cm) was also significantly lower in UR independently of sex: W-R 110.6 ± 12 versus W-UR 98.5 ± 8 (p < 0.05); M-R 113.9 ± 15 versus M-UR 87.4 ± 9 (p <0 .005). Insulinemia (UI/ml) was significantly lower in M-UR than in M-R (16.1± 8 versus 9.4 ± 7, p<0.005) but not in women. Also significant differences were found in leptin levels (pg/ml) in men but not in women (M-R 1824.0 ± 1139 versus M-UR 477.6 ± 692; p < 0.05). No differences were observed in the number of antipsychotics received before CLZ, months of untreated psychosis, fasting glycemia, trygliceridemia, HDL cholesterol, CRP, HbA1c and diastolic or systolic arterial blood pressure.DiscussionTime to CLZ initiation could be a critical factor predisposing to UR. The absence of clozapine-induced abdominal obesity and changes in BMI are also to be associated with poor clinical response, independently of plasma drug levels. Differences between ultra-resistant men and women concerning insulin and leptin plasma levels should be further investigated. As far as we know, this is the first paired case-control study aimed to investigate factors associated with CLZ resistance in schizophrenia.

Fatores de risco associados à esquizofrenia resistente ao tratamento em primeiro episódio psicótico

Objective: The risk factors for treatment-resistant schizophrenia (TRS) in first-episode psychosis (FEP) remain unclear. The aim of this study was to investigate risk indicators for TRS in FEP. Methods: A total of 53 patients with FEP and a diagnosis of schizophrenia were selected among individuals seen at the psychiatric ward of Hospital das Clinicas Luzia de Pinho Melo between 2011 and 2015. Upon admission, subjects were evaluated with the Positive and Negative Syndrome Scale (PANSS) and received initial treatment for 4 weeks. Patients showing < 40% reduction on PANSS in response to antipsychotic treatment had the drug changed, and the scales were applied again after 4 weeks. After failure with two antipsychotics, at full doses, for 4 weeks each, clozapine was introduced, and the patient was considered to have TRS. Logistic regression was performed including gender, age at onset, duration of untreated psychosis, substance use, global assessment of functioning at baseline and totalPANSS at baseline as independent variables, and TRS as the dependent variable. Results: Duration of untreated psychosis presented significance at p = 0.038 and Exp (B) = 4.29; for total PANSS, results were p = 0.012 and Exp (B) = 1.06. Conclusion: Identifying factors associated with early resistance to treatment could allow clinicians to avoid delays in the introduction of clozapine and prevent worse prognosis for these patients.

Clozapine-induced myocarditis: characterisation using case-control design

Purpose: Myocarditis is a hypersensitivity reaction, typically occurring in the third week after commencing clozapine, the most effective treatment available for schizophrenia. The signs and symptoms of myocarditis are notoriously difficult to distinguish from those associated with initiation of clozapine. A case-control design is commonly used to investigate risk factors, we show that it can be used to identify features which assist in the diagnosis of myocarditis. Methods: Cases and controls were documented from patients' medical records. Controls were matched by unit at which clozapine was commenced and approximate start date. Results: 105 cases and 296 controls met entry criteria. Time to onset for cases was 10-33 days, with 82% developing 14-21 days after commencing clozapine. Almost 90% of cases and controls had tachycardia. Eosinophilia developed in 64% of cases and 30% of controls, but onset among cases was delayed 0-8 days after the peak in troponin. However, 87% of cases had C-reactive protein (CRP) > 50mg/L and CRP could be raised up to 5 days before the rise in troponin. Multivariate regression analysis indicated that the risk of myocarditis increased with increasing age (31% per decade; 95% CI 7-60%), increasing rate of clozapine dose titration (26% per 250mg during days 1-9; 95% CI 2-55%) and concomitant sodium valproate (odds ratio 2.59; 95% CI 1.51-4.42). Conclusion: Comparison of cases and controls permitted identification of the features of myocarditis, and avoided confounding by features associated with introduction of clozapine. Monitoring for myocarditis should use troponin and CRP but not eosinophil counts. Clozapine should be introduced by slow dose titration and sodium valproate is best avoided, if clinically feasible.

Safety and efficacy of combined clozapine–azathioprine treatment in a case of resistant schizophrenia associated with Behçet's disease: a 2-year follow-up

Behçet's disease (BD) is a recurrent inflammatory disorder involving multisystems of the body. Neuropsychiatric symptoms, like psychosis and depression, often occur in BD, but the safety and efficacy of combined clozapine–azathioprine treatment have never been assessed. We here report on a 37-year-old man with BD and treatment-resistant schizophrenia who obtained an improvement following the introduction of clozapine in addition to azathioprine, without developing agranulocytosis or other severe adverse side effects during a 2-year follow-up.

Clozapine is underutilized.

I read the piece by Wang and Li[1] with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory schizophrenia and clinically significant suicidality. Despite the evidence that 25-40% of patients with schizophrenia would be candidates for clozapine based on labeled indications, approximately 5% of patients with schizophrenia are receiving it. Clozapine was approved by the Food and Drug Administration in the United States in 1989 following a large-scale clinical trial we conducted in 1988[2] demonstrating clozapine's superiority over chlorpromazine in carefully selected treatment refractory patients who had undergone a prospective trial of high dose haloperidol in order to confirm their lack of response. Over the subsequent two decades clozapine's superiority has been confirmed in several government-funded studies.[3]–[5] Despite the introduction of other so called ‘atypical’ or second generation antipsychotics, no other compound—even those with similar chemical structures—has consistently replicated clozapine's effects. Although clozapine has been shown to be superior in patients who have failed on other medications, there is no evidence that clozapine is superior as a first-line medication. At the same time, however, it is possible that waiting until a patient fails adequate trials of three different medications is too conservative an approach; these patients may be waiting too long to try an effective treatment. Unfortunately, there is insufficient research to establish the optimum point in an individual's treatment history to introduce clozapine. It is certainly possible that the introduction of clozapine after one fully adequate failed trial of an antipsychotic medication (with confirmed adherence and therapeutic blood levels) would be sufficient. If this proved true it would be particularly valuable in the first episode of illness or in the first years after onset of illness as it would increase the likelihood of a timely treatment response. Clozapine's use has been somewhat constrained by the requirement for weekly blood monitoring in order to detect the presence of agranulocytosis. The risk of true agranulocytosis appears to have declined since the early years of clozapine use, and new methods for managing this condition has reduced fatality rates enormously. Nevertheless, the management of clozapine's side effects continues to be a challenge. Though progress is being made in identifying individuals at high risk for agranulocytosis[6] this still remains an obstacle for some physicians and patients. The risk of metabolic side effects is also very real and needs to be considered in any management plan. The appropriate or optimum dosing of clozapine also remains a challenge. Dosage patterns vary considerably from country to country. Though some studies provide guidance regarding therapeutic blood levels it is likely that there are ethnic differences in these relationships as well. Clearly, as suggested by Wang and Li,[1] more research is necessary to achieve the goals of personalized medicine in the use of a drug like clozapine, where both the potential rewards and risks are higher than usual. Some clinicians and policy makers attribute the underutilization of clozapine to its side effect profile and, therefore, patient resistance to its use. However, it is often the case that physicians project their own concerns about the possible serious side effects of clozapine onto patients and make assumptions about patients' desires without an appropriate process of shared decision-making. Moreover, many physicians in the United States and in China appear more comfortable with antipsychotic drug polypharmacy than with clozapine monotherapy, despite the fact that polypharmacy has not been adequately established as an appropriate strategy for the treatment of refractory patients. The fact that clozapine utilization varies as much as it does from country to country underscores the variety of factors that contribute to its use. Many clinicians are inadequately informed about the evidence base for the use of clozapine and about the strategies necessary for managing its potential adverse effects. Further training about clozapine is necessary. But there is also a need for research on implementation. How can the field of psychiatry better succeed at promulgating the use of evidence-based practices?

Effects of Olanazapine and Haloperidol on Serum Malondialdehyde, Prolactin Level, Blood Glucose and Lipid Profile in Schizophrenic Patients

Background and objective: The association of the atypical antipsychotics with hypergly-cemia, elevated lipids, and weight gain was recognized soon after the introduction of clozapine and has become of increased concern as the use and uses of atypical antipsy-chotics have been expanded. The aim of the present study was to investigate the preva-lence of diabetes, dyslipidaemia, lipid peroxidation and hyperprolactinemia in Olanzepine treated patients in comparison with patients treated with haloperidol. Methods: Fifty patients were selected randomly from psychiatric inpatient clinic in Erbil city in Iraqi Kurdistan Region between November 2007 and June 2008. All patients were diagnosed as schizophrenia, and none of them were in acute severe state. Thirty Schizophrenic patients received Haloperidol orally as typical antipsychotic and 20 patients received Olanazapine orally as atypical antipsychotic for a minimum of one month. Fasting blood samples for the assessment of serum malondialdehyde (MDA), lipid profile, fasting blood glucose (FBG) and prolactin levels were obtained after one month of the drug prescribing time. From those fifty patients, 16 patients were selected to follow them prospectively over a mean period of time of 112 days for olanzapine and 75 days for haloperidol. The prospective study includes FBG, lipid profile, BMI and serum MDA. Results: The prevalence of hyperprolactinaemia and lipid peroxidation was higher in Haloperidol treated patients. Whereas, the prevalence of diabetes and dyslipidaemia were higher in Olanazapine treated patients, The mean level of BMI of the Olanazapine group was significantly higher than BMI of the Haloperidol group. There was 6.66 % prevalence of DM in Olanazapine treated patients, but there was no prevalence of DM in Haloperidol treated patients. There was no incidence of diabetes mellitus in the prospective study for both Haloperidol and Olanazapine treated patients. Conclusion: No absolute evidence indicates that the atypical antipsychotic Olanazapine is the cause of diabetes, since the glucose levels of all patients were within normal range and there was no incidence of diabetes in the prospective study in spite of their higher weight and body mass index.

Withdrawal-Emergent Respiratory Dyskinesia with Risperidone Treated with Clozapine

Back to table of contents Previous article Next article LETTERFull AccessWithdrawal-Emergent Respiratory Dyskinesia with Risperidone Treated with ClozapineDattatreya Namdeorao Mendhekar M.D., D.P.M,Amir Inamdar Dip.Pharm.Med, DNB(Psy),Dattatreya Namdeorao Mendhekar M.D., D.P.MSearch for more papers by this author,Amir Inamdar Dip.Pharm.Med, DNB(Psy)Search for more papers by this author,Published Online:1 Apr 2010https://doi.org/10.1176/jnp.2010.22.2.247.e24AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We report the case of a woman with schizophrenia who developed withdrawal-emergent respiratory dyskinesia with risperidone. Reintroduction of risperidone resulted in complete remission but led to the development of tardive dyskinesia. Introduction of clozapine after withdrawal of risperidone yielded marked improvement in the respiratory dyskinesia, tardive dyskinesia, and psychosis. Case ReportA 64-year-old woman with DSM-IV schizophrenia for 12 years presented to us with a relapse. She was variously treated with trifluoperazine, 15 mg/day, chlorpromazine, 500 mg/day, and thioridazine, 300 mg/day, before presenting to us, but continued to exhibit relapses. After choosing to remain off her medications for 5 months, she had a relapse and risperidone, 2 mg/day, was started; this dosage was increased to 4 mg/day along with trifluoperazine, 2 mg/day, over a period of 4 weeks. She remained stable on this regimen for 3 months. At this time, the patient had an episode of viral fever and hence stopped these medications abruptly, on her own. Within 36 hours, she developed severe oro-bucco-lingual dyskinetic movements with involuntary movements of respiratory muscles, grunting and irregular breathing pattern, as if she was breathless after exercise. She had difficulty maintaining a sitting posture due to hyperventilation. Movements were involuntary, and distraction would not alter their intensity. No abnormal movements were noticed during sleep or in any other part of her body. Clinical examination did not reveal any contributory findings, and all routine investigations, including a chest X-ray, were normal. She scored 10 on the Abnormal Involuntary Movement Scale (AIMS). Separate trials of trihexyphenidyl, 4 mg/day, clonazepam, 2 mg/day, and clozapine, 150 mg for 7 days, failed.Risperidone, 2 mg/day, was restarted and increased to 4 mg/day over 10 days; she exhibited a dramatic response after 4 days of therapy, and her involuntary movements disappeared. At the end of 12 weeks of risperidone treatment, 4 mg/day, she developed dyskinetic movements of both hands, but with more on the right suggesting tardive dyskinesia. Risperidone was withdrawn, and, as a result, the patient again exhibited (withdrawal) respiratory dyskinesia. Her psychosis also relapsed. Hence, clozapine, 25 mg/day, was started as we assumed it would be beneficial in tardive dyskinesia, respiratory dyskinesia, and psychosis. The dosage was increased to 250 mg/day over 3 weeks. After 6 weeks of clozapine therapy, she showed marked improvements in all her symptoms with complete disappearance of the respiratory dyskinesia. The probability of an adverse drug reaction was assessed using the Naranjo Probability Scale which indicated a possible association between risperidone withdrawal and respiratory dyskinesia.Discussion We have come across only three case reports of possible withdrawal-emergent (respiratory) dyskinesia associated with risperidone. 1 – 3 However, to the best of our knowledge, the use of clozapine in cases with respiratory dyskinesia has not been reported in the literature. Therefore, this is probably the first case report where clozapine had been used successfully in neuroleptic withdrawal-induced respiratory dyskinesia. It is not advisable to administer the same neuroleptic again, as the occurrence of withdrawal dyskinesia may predict vulnerability to the development of tardive dyskinesia. 4 Nevertheless, clozapine, with low affinity for the striatal D2 receptors and to the inhibition of presynaptic 5HT-2A receptors together with its anticholinergic activity, may be less likely to induce extrapyramidal side effects. 4Department of Psychiatry, Neuropsychiatry and Headache Clinic, Delhi, IndiaGlaxoSmithKline R&D, Essex, U.K.

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

After the introduction of clozapine in 1990, second-generation-or atypical-antipsychotics were thought to be more effective, safer, and less costly than first-generation-or typical-antipsychotics. However, only limited evidence on the efficacy and safety of atypicals was available. Because of this knowledge gap, the National Institute of Mental Health sponsored the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) to compare first- and second-generation antipsychotics. The CATIE trial found that antipsychotic drug treatments are generally effective overall but have various limitations as reflected by high rates of discontinuation due to both efficacy and tolerability problems. In addition, the trial found that conventional agents with intermediate potency were comparably effective with atypical agents.

EPS Profiles: The Atypical Antipsychotics

Within the first few years after chlorpromazine began to be used to treat psychosis, it was observed that it could cause many kinds of neurologic reactions that resembled those seen in idiopathic Parkinson's disease. These reactions were termed "extrapyramidal side effects" (EPS) because of their resemblance to the signs of Parkinson's disease, which were associated with degeneration of the dopamine nerve tracks located in the extrapyramidal region of the central nervous system. Eventually this association of dopamine loss, antipsychotics, and parkinsonism became a central part of the dopamine hypothesis of schizophrenia. Unfortunately, this association was also used to support the hypothesis that EPS were absolutely necessary for antipsychotic efficacy--hence the term "neuroleptic" rather than "antipsychotic." This theory, now discredited, was used to justify the practice of inducing EPS as a means to gauge whether an antipsychotic would be effective. The demonstration that clozapine, an antipsychotic virtually devoid of EPS, has better efficacy for psychosis than any other "neuroleptic" disproved the theory that EPS were fundamentally linked to efficacy. Because the idea of a relationship between EPS and efficacy was so ingrained in clinical practice, clozapine was called "atypical." Our understanding of the relationship between EPS and antipsychotic response has come full circle. With the introduction of clozapine and other newer antipsychotics, it has become clear that EPS are harmful and serve no beneficial purpose. The availability of newer antipsychotics with a lower EPS burden means that, at least in theory, it is now possible to treat psychosis without EPS in the vast majority of patients. In practice, however, EPS remain a significant problem even in the era of atypical or second generation antipsychotics (SGAs). One limitation is that the concept of "atypicality," when used to denote antipsychotic efficacy without EPS, is a relative not an absolute concept. Because all of the post-clozapine SGAs still affect the dopamine D2 receptor, it may be more accurate to say these medications have lower EPS liabilities that the earlier "neuroleptic" antipsychotics; i.e., relatively fewer patients will get EPS at therapeutic doses of one of the newer medications and, when EPS do occur, they tend to be less severe. Nonetheless, reduced EPS are not the same as no EPS, and most of the newer antipsychotics can still cause EPS in some patients. The incidence of EPS differs among the SGAs, with risperidone associated with the most and clozapine and quetiapine with the fewest EPS. The likelihood of developing EPS with a first-line SGA depends not only on the specific agent, but also on the rapidity of dose escalation, the target dose, and the patient's intrinsic vulnerability to EPS. Even with the SGAs, clinicians should not be lulled into believing EPS cannot happen, but need to be able to recognize and manage both overt and subtle manifestations of EPS. This review discusses differences among the SGAs in EPS liability, relationships between dosing and type of EPS, and situations in which differences in EPS liability among the SGAs are clinically relevant.

Medication-Induced Weight Gain and Dyslipidemia in Patients With Schizophrenia

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Evolution of Antipsychotic Intervention in the Schizophrenic Psychosis

The accidental discovery (in the 1950s) and subsequent development of antipsychotic drugs have revolutionized the care of many patients with the schizophrenic psychoses. The first-generation antipsychotics, though effective for hallucinations, delusions, as well as a treatment of the disorder in two-thirds of patients with schizophrenia, burdened many patients with extrapyramidal effects (EPS), including dystonias, akathisia, and pseudo-Parkinsonian morbidity. Moreover, they had little or no effect on the most disabling, core symptoms associated with withdrawal of interests and interpersonal relationships. The second-generation antipsychotics, which began to appear in the late 1980s with the introduction of clozapine, had strikingly less morbidity, contributing little or no EPS and providing at least modest promise of reduction of negative symptoms and enhancement of some aspects of cognition. However, some second-generation antipsychotics have induced considerable weight gain, and appear to lower the threshold for the development of the metabolic syndrome, which increases cardio-vascular morbidity. The actual mechanism(s) of action of the antipsychotic drugs is still in dispute. Direct and indirect effects on dopamine transmission have been supported by much of the evidence. Direct blockade of dopamine hyperactivity and partial restoration deficient dopamine has been the standard explanation of their effects. However, dysfunctional intracellular signal transduction and dysfunction of myelin are emerging as competing pathologies upon which antipsychotics act. It is likely that the next generation of antipsychotics will act more directly and more specifically on such underlying neuropathology.

Clozapine-Induced Tardive Dyskinesia and Hypothyroidism

Back to table of contents Previous article Next article LETTERFull AccessClozapine-Induced Tardive Dyskinesia and HypothyroidismD.N. Mendhekar M.D., D.P.M.,Harpreet S. Duggal M.D., D.P.M.,D.N. Mendhekar M.D., D.P.M.Search for more papers by this author,Harpreet S. Duggal M.D., D.P.M.Search for more papers by this author,Published Online:1 Apr 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: With the advent of atypical antipsychotics, the prevalence and incidence of tardive dyskinesia are on the decline. However, the literature is spotted with anecdotal reports of tardive dyskinesia associated with atypical antipsychotics. Clozapine, the only atypical antipsychotic shown to be effective for tardive dyskinesia in controlled studies, has been shown to cause tardive dyskinesia on rare occasions. 1 The authors report a similar case and also discuss the putative interaction of hypothyroidism and the dopaminergic system in the expression of tardive dyskinesia. Case ReportMrs. A, a 47-year-old woman, was diagnosed with schizophrenia of 6 years’ duration. Her symptoms were characterized by hallucinatory behavior, delusions of persecution, decreased personal care and withdrawn behavior. A year after the onset of illness, she was also found to have hypothyroidism as her thyroid stimulating hormone level was raised (29 mU/liter; normal range=0.4–6 mU/liter). At that time she was started on levothyroxine 50 mcg daily (increased to 100 mcg daily) and trifluoperazine 15 mg. daily. This combination was continued for a year, and subsequently trifluoperazine was replaced by risperidone 9 mg daily without a favorable result. Hence, risperidone was stopped after continuing it for about 10 months. She also had a brief trial of haloperidol but had poor drug adherence due to extrapyramidal side effects. Subsequently, the patient was started on clozapine, titrated to 150 mg daily while the levothyroxine was continued at 100 mcg. daily. She showed a marked improvement in positive as well as negative symptoms, and her thyroid profile continued to remain normal. Seven months after starting clozapine, she exhibited horizontal grinding movements of the lower jaw and dyskinetic movements of the tongue. These movements would subside temporarily on bringing these to patient’s attention. She scored 9 on Abnormal Involuntary Movement Scale (AIMS). Speculating that levothyroxine may be contributing to the movement disorder, it was stopped for 8 weeks without any effect on the movements or the AIMS score, but her thyroid stimulating hormone level increased again (16 mU/liter). Levothyroxine was again added to clozapine, and within 6 weeks her thyroid profile returned to normal. Her neurological examination, other than that for the dyskinetic movements, was unremarkable and so was a head computed tomography scan and an electroencephalogram. A sequential trial of propranolol 80 mg daily and tetrabenazine 125 mg daily did not ameliorate the dyskinesia. The patient was subsequently deemed to have developed tardive dyskinesia and met DSM-IV criteria for this condition. An attempt was made to reduce the dose of clozapine from 150 mg daily to 125 mg daily but was limited by worsening of psychotic symptoms resulting in the patient ending up on a higher dose than before (200 mg daily). Neither reduction nor increase in the dose of clozapine showed any improvement in the dyskinetic movements, and the patient continues to exhibit these movements.Comment To our knowledge, there have been no reports associating clozapine-induced tardive dyskinesia and hypothyroidism. Although it can be argued that this patient may have developed withdrawal dyskinesia on discontinuing typical antipsychotics or risperidone, the temporal correlation between the introduction of clozapine and appearance of tardive dyskinesia favors clozapine as the likely etiology in this patient. It would be interesting to explore if the effect of thyroid hormones on the dopaminergic system may contribute toward appearance of tardive dyskinesia in patients on antipsychotics. Hypothyroidism has been associated with subsensitivity of striatal dopamine receptors, 2 and thyroid hormones potentiate dopaminergic behavior. 3 A study carried out in rats treated with haloperidol revealed significant upregulation of dopamine receptors in hypothyroid rats compared to hyperthyroid rats. 4 Furthermore, there is a report of tardive dyskinesia associated with sulpiride, a dopamine receptor antagonist, in a patient with hypothyroidism. 5 Interestingly, a report also indicates exacerbation of orofacial dyskinesias with nomifensine, a dopaminergic antidepressant, in an elderly woman with hypothyroidism. 6 Thus, future research into the complex interplay of the dopaminergic system and thyroid dysfunction in the expression of tardive dyskinesia is encouraged. Private practice, Delhi, IndiaWestern Psychiatric Institute and Clinic, Pittsburgh, PA

Recovery From Schizophrenia: A Concept in Search of Research

Recovery From Schizophrenia: A Concept in Search of Research