Olanzapine Therapy Research Articles

Delirium Associated with Olanzapine Therapy in an Elderly Male with Bipolar Affective Disorder

Atypical antipsychotic medications are commonly used to treat symptoms of delirium. Olanzapine has been successfully used in the treatment of delirium. However, there have been few case reports of delirium associated with olanzapine. We hereby report a case of delirium associated with olanzapine therapy. Possible risk factors and underlying pathogenesis is discussed.

P03-331 - Neuroleptic malignant syndrome associated with olanzapine therapy

ObjectivesNeuroleptic Malignant Syndrome (NMS) is a rare and potentially lethal adverse reaction generally associated with typical antipsychotics. Cardinal features include muscle rigidity, hyperthermia, mental status changes, elevated CPK levels.MethodsWe report on a patient receiving olanzapine, an atypical antipsychotic, who developed NMS.ResultsA 31 year-old male with a 5 year history of paranoid psychosis, was successfully treated with olanzapine 15 mg per day. He was also receiving oxcarbazepine for epilepsy (1200 mg/ day) and also suffered from spastic congenital paraparesis. He was almost asymptomatic for 4 years. At some point there was a recurrence of his illness with restlessness and aggressive behaviour. The patient decided to receive additionally 5 mg of olanzapine,without consulting psychiatrist. Soon he developed hyperthermia, hypertonia and confusion. He was initially admitted in a general hospital with leukocytosis and elevated CPK levels (1999 U/L). Other laboratory examinations were within normal limits. He was treated with ceftriaxone and parenteric fluids. After 48 hours he was improved and olanzapine was reinitiated (10 mg/day), and a few hours later he developed fever (40' C), hypertonia, dysphagia, confusion, CGS: 7/15 and elevated CPK levels (4900 U/LT). He was then transferred to the Intensive Care Unit and received treatment for NMS with bromocryptine and dantrolene sodium. His temperature returned to normal in two days and in 6 days he was physically stable. Twenty days later he received treatment for psychosis with low dose quetiapine.ConclusionNMS characterized by muscular rigidity and fever may rarely occur with atypical neuroleptics, such as olanzapine.

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

Psychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for clinical treatment decisions given the fact that olanzapine serum concentrations correlated with treatment response. Side effects and weight gain, however, seem to be more influenced by serotonergic polymorphisms.

Aripiprazole for the Management of Olanzapine-induced Weight Gain

Weight gain is an important side effect of olanzapine. One therapeutic strategy might be the add-on of aripiprazole, a partial dopaminergic and serotonergic agonist. Here, we report on four patients who experienced a significant reduction of body weight after aripiprazole was added in a mean dose of 13.8 mg/day to the preexisting olanzapine therapy and olanzapine was reduced from a mean dose of 17.5 to 11.3 mg/day. We did not observe significant changes in fasting glucose, triglycerides, and cholesterol. This approach might increase safety, tolerability and patient's adherence to olanzapine treatment and should be further evaluated in controlled trials.

Olanzapine Induced Acute Meige's Syndrome

Back to table of contents Previous article Next article LETTERFull AccessOlanzapine Induced Acute Meige’s SyndromeDattatreya Namdeorao Mendhekar M.D., D.P.M.,Leonora War M.D., M.R.C.Psych.,Dattatreya Namdeorao Mendhekar M.D., D.P.M.Search for more papers by this author,Leonora War M.D., M.R.C.Psych.Search for more papers by this author,Published Online:1 Apr 2009https://doi.org/10.1176/jnp.2009.21.2.225AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Meige’s syndrome is a focal dystonia involving blepharospasm and oromandibular dystonia. The typical feature of this disorder is the involvement of orbicularis oculi muscle. Since blepharospasm interferes with vision-dependent activities, this syndrome may cause disability. Electronic and manual search revealed only two cases of Meige’s syndrome associated with atypical antipsychotic drug (i.e., risperidone and quetiapine). 1 , 2 No information is available on other atypical antipsychotics related to Meige’s syndrome. We wish to report a case of a woman with schizophrenia who developed Meige’s syndrome after initiation of olanzapine therapy. To our knowledge this is the first case of olanzapine-induced Meige’s syndrome in the existing literature. In contrast, there are two published case reports in which typical antipsychotic-induced Meige’s syndrome was treated successfully with olanzapine. 3 – 4Case ReportMrs. A, a 47-year-old married woman, fulfilled the DSM-IV criteria for paranoid schizophrenia. She had no family history of neurological and medical disorder. Her illness began when she was 44 years old. Her symptoms were characterized by persecutory delusion, withdrawn behavior, muttering to self, and decreased personal care. Childhood history and personal history did not reveal any symptoms suggestive of cerebral insult. She was initially treated with tablet trifluoperazine, 15 mg/day, but developed akathisia. Hence the trifluoperazine was replaced with clozapine, 200 mg/day. While being treated with clozapine for 8 weeks, Mrs. A developed sialorrhoea which disappeared after complete withdrawal of clozapine. She remained drug free for 6 months but she had a relapse of psychotic illness. This time, treatment with tablet olanzapine, 7.5 mg/day, was begun. On day 7 of olanzapine therapy, she exhibited both blepharospasm and oromandibular dystonia and had difficulty keeping both her eyes open. She also expressed her inability to speak and eat due to dystonic movements. Further, she was unable to perform vision-dependent tasks such as watching TV or cooking. The blepharospasm was exaggerated with stress, anxiety, and by looking upward. No abnormal movements were noticed in other parts of the body. Ophthalmological and neurological examination did not reveal any other significant findings. Olanzapine was discontinued and replaced by trihexyphenidyl, 4 mg, and clonazepam, 2 mg. Marked resolution of symptoms were noticed within 7 days after the withdrawal of olanzapine. There was no relapse of psychotic symptoms noticed for the next 6 months and she was maintained only on clonazepam, 1 mg/day.Discussion Meige’s syndrome is one of the extrapyramidal syndromes that appears after long-term use of antipsychotic and it is believed that it is difficult to treat. 5 In this case, temporal relation between olanzapine administration, the appearance of characteristic dystonic reaction in the absence of choreoathetotic movements, and the prompt response to anticholinergic drugs can easily rule out idiopathic Meige’s syndrome. One might argue that that the remission of Meige’s syndrome was due to simple withdrawal of olanzapine and not because of the effect of trihexyphenidyl. This report suggests that Meige’s syndrome can occur even with atypical antipsychotics as an acute side effect and if diagnosed early, the withdrawal of causative neuroleptic can aid rapid recovery. Neuropsychiatry and Headache Clinic, Delhi, IndiaPsychiatrist, Edmonton, Alberta, Canada

Rhabdomyolyse et élévation des enzymes musculaires sous olanzapine

Introduction “Atypical” antipsychotics tend to replace traditional antipsychotics as first line therapy for psychotic disorders, due to their better side-effect profile with fewer extrapyramidal manifestations, allowing a better observance. Nevertheless, second-generation antipsychotics may also lead to adverse events such as metabolic disorders, agranulocytosis or muscle damage. Cases of rhabdomyolysis (aside neuroleptic malignant syndrome) have been reported in patients receiving olanzapine (Zyprexa ®). Methods We reviewed the cases of olanzapine induced rhabdomyolysis reported to the French national database of drug adverse events and retrieved additional cases published in the medical literature. Results We collected 13 cases from the French pharmacovigilance database and eight additional cases from the literature. Seventeen patients needed hospitalization. Creatine kinase (CK) rate ranged between 413 and 34,500 UI/L. Outcome was favorable in 85% of the cases (17 out of 20 cases) after discontinuation of olanzapine. Conclusion Although rhabdomyolysis is a rare side effect (< 1%) of olanzapine, this adverse event should be evoked when a patient with olanzapine presents with muscle pain, unexplained fatigue or weakness. Prompt dosage of CK should be performed. However, it remains uncertain whether a mild and asymptomatic muscle enzyme increase without any metabolic disorder requires the discontinuation of olanzapine therapy.

Potential Effect of Olanzapine on Total Antioxidant Status and Lipid Peroxidation in Schizophrenic Patients

Olanzapine is an atypical antipsychotic drug used in the treatment of schizophrenia. Controversial results have been obtained measuring different serum antioxidant enzymes and serum malondialdehyde (MDA) in schizophrenic patients treated with olanzapine. The aim of this study is to find the effect of olanzapine on total antioxidant status (TAS) and lipid peroxidation in schizophrenic patients. Thirty schizophrenic patients were treated orally with olanzapine (10–20 mg/day) for 2 months. Thirty healthy subjects were also included as a control group. Blood samples were taken from patients before and after olanzapine therapy, and analyzed for serum TAS and MDA. In schizophrenic patients, mean values of pretreatment serum TAS were significantly less (difference = 37.4% of control) than the control value, whereas serum MDA levels were significantly higher (difference = 176% of control) than the control values . Olanzapine treatment for 2 months significantly increased serum TAS levels (37.8%) and reduced serum MDA levels (22.2%) in comparison to respective pretreatment values. In conclusion, the data suggest that olanzapine therapy for 2 months at least partially ameliorates adverse effects on the antioxidant defense mechanism in schizophrenia.

Refractory Restless Legs Syndrome Likely Caused by Olanzapine

We report a case of severe restless legs syndrome (RLS) that occurred as a side effect of olanzapine therapy. It was refractory to treatment with 2 mg of clonazepam and 3 mg ropinirole. There was partial relief with propoxyphene, however, it was stopped because of side effects. The symptoms disappeared once olanzapine was switched to another antipsychotic medication. Only two prior published reports associate olanzapine usage with development of RLS. In one report, low-dose benzodiazepines and ropinirole were associated with resolution of RLS symptoms stating dopamine depletion as the likely etiology. In our patient, however, RLS due to olanzapine was refractory to the trial of both high-dose benzodiazepine and ropinirole. This suggests that RLS occurring as a side effect of olanzapine therapy may have additional causative mechanisms beyond simple dopamine depletion as postulated before. High-dose narcotics, if tolerated, may be an alternative in such refractory cases.

Status epilepticus in a patient treated with olanzapine and mirtazapine

Few cases of seizures associated with olanzapine therapy and even fewer with mirtazapine have been published, most of them in patients with confounding risk factors. Our objective was to report a case of Status epilepticus in a patient receiving olanzapine and mirtazapine, with no previous history of seizure and no confirmed underlying cause for seizure. A 48-year-old white, psychotic woman developed generalized tonic-clonic seizures that progressed to Status epilepticus during hospitalization. 4 days before the incident, mirtazapine (30 mg) was added to the treatment, while 2 days before the incident, the treatment switched from quetiapine to olanzapine, and mirtazapine was increased to 60 mg. No other toxic, metabolic, electrolyte or anatomic abnormality was identified. After discontinuation of olanzapine, the patient remained seizure-free. To our knowledge, this is the second reported case of Status epilepticus that has been associated with the use of olanzapine, while only one report of seizures, but none of Status epilepticus connected to mirtazapine is found in the literature. Although olanzapine has infrequently been associated with epileptogenic risk, it should be used cautiously especially when concomitant medication or other predisposing factors exist.

Factors associated with weight gain during olanzapine treatment in patients with schizophrenia or bipolar disorder: Results from a six-month prospective, multinational, observational study

The aim of this 6-month observational study was to examine which clinical, eating- and lifestyle-related factors were associated with weight gain in patients initiating or switching to oral olanzapine for the treatment of schizophrenia or bipolar mania. A total of 622 outpatients in four countries (China, Mexico, Romania, Taiwan) were assessed at monthly intervals for up to 6 months. Mixed model repeated-measures analysis, adjusted for baseline weight, was used to identify which factors were associated with weight gain during olanzapine therapy. After 6 months of therapy, the LS mean weight change was +4.1 kg and 43.9% of the patients had significant (≥7%) weight gain. Early significant weight gain after 2 months of therapy occurred in 23.4% of the patients and these patients gained significantly more weight overall. Ten factors were associated with weight gain during 6 months of olanzapine therapy in an exploratory multivariate analysis: country, housing conditions, stronger appetite, excessive amount of food needed to feel full, eating until uncomfortably full, thoughts preoccupied with food, meal location, increased meal frequency, evening snack consumption, and a lower amount of vigorous exercise. These results indicate that the influence of environmental, eating- and lifestyle-related factors should be considered when assessing weight gain during olanzapine therapy.

Entomophagy and Coprophagy in Undifferentiated Schizophrenia

Coprophagia or the ingestion of feces, considered to be a variant of pica, has been associated with medical disorders like seizure disorders, cerebral atrophy, and tumors and with psychiatric disorders like mental retardation, alcoholism, depression, obsessive compulsive disorder, schizophrenia, schizoaffective disorder, fetishes, delirium, and dementia. But entomophagy or the practice of eating live or dead insects as food by humans has only been reported as part of eating habits by some cultures in the world and not in association with any medical or neuropsychiatric disorders. Till date, there is no report in medical literature of entomophagy as an association with any neuropsychiatric or medical illnesses. Coprophagy and entomophagy has not been together reported as well. We describe the first ever case report of a 19-year- old male patient diagnosed with undifferentiated schizophrenia and associated with both entomophagy and coprophagy. His schizophrenic symptoms, the entomophagic, coprophagic behaviors improved with olanzapine therapy. Entomophagy and coprophagy, two very unusual human behaviors, can be seen in association with schizophrenia.

Pedal edema with olanzepine

Olanzapine, an atypical antipsychotic is considered superior to its conventional congeners. Here we report two cases of pedal edema secondary to olanzapine. In both cases the systemic causes of pedal edema were ruled out. On reducing the dose of olanzapine, pedal edema regressed and completely resolved after stopping the drug. So we attribute the edema to olanzapine therapy. As the definitive cause and further consequences of pedal edema are not known, hence stringent monitoring of adverse effects of this drug is required.

Early effects of olanzapine on serum levels of adiponectin and leptin in schizophrenic patients

Objective To explore the early effects of olarmapine on body weight,serum levels of glucose,lipid ,adiponeetin and leptin in schizophrenic patients.Methods Twenty patients with schizophrenia who were treated in the department of psychiatry of the Third affiliated Hospital of Sun Yat-sen University were recruited into our study.All the patients have been initiated with a stable dose of olanzapine for six weeks.The height,weight,fasting blood glucose,lipid,adiponectin and leptin levels were investigated at the baseline and at six weeks.Results The weight(65.06±9.91)kg,BMI (23.91±3.01)kg/m2,blood triglyeeride (2.15±0.15)mmool/L,cholesterol(5.91±1.47)mmol/L increased significantly after six olanzpine treatment (P<0.05),adiponectin(45.14±16.72)μg/ml and leptin levels (9.55±3.36) ng/ml increased significantly after treatment (P<0.05).Spearman correlation analysis indicated that leptin is positively correlated with weight after six weeks (r=0.560,P=0.046).Conclusion Weight gain and lipid metablism disorder were considered to be an early change of the treatment of olanzapine.Meanwhile,adiponeetin and leptin levels increased after initiation of olanzapine therapy,suggesting that they played some role against APs associated-weight gain and lipid metabliam disorder.

Pharmacokinetics of olanzapine in Chinese male schizophrenic patients with various smoking behaviors

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose–plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers ( n = 9), light-smokers (1–4 cigarettes per day; n = 9), and heavy-smokers (≥ 5 cigarettes per day; n = 9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers ( n = 9; 0.79; p = 0.01) or combined with light-smokers ( n = 18; 0.62; p < 0.01) between peak plasma olanzapine concentrations ( C max ) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC 0→120 by 45.1% in light-smokers. The mean C max and the mean area under the plasma concentration–time curve from time zero to 120 h (AUC 0→120) of the heavy-smoking patients was 9.3 ± 4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4 ± 167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50–100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.

Successful Treatment of Hallucinations Associated With Sensory Impairment Using Gabapentin

Successful Treatment of Hallucinations Associated With Sensory Impairment Using Gabapentin

A 16 WEEK RANDOMIZED DOUBLE-BLIND, DOUBLE-DUMMY TRIAL OF SUBLINGUALLY DISINTEGRATING OLANZAPINE VS. STANDARD OLANZAPINE TABLETS IN PATIENTS WHO GAINED WEIGHT DURING OLANZAPINE

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose–plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers (n = 9), light-smokers (1–4 cigarettes per day; n = 9), and heavy-smokers (≥ 5 cigarettes per day; n = 9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers (n = 9; 0.79; p = 0.01) or combined with light-smokers (n = 18; 0.62; p < 0.01) between peak plasma olanzapine concentrations (Cmax) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC0→120 by 45.1% in light-smokers. The mean Cmax and the mean area under the plasma concentration–time curve from time zero to 120 h (AUC0→120) of the heavy-smoking patients was 9.3 ± 4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4 ± 167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50–100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.

Effects of risperidone and olanzapine on remnant-like lipoprotein particle cholesterol (RLP-C) in schizophrenic patients

Second generation antipsychotics are associated with the risk of metabolic disorders such as diabetes mellitus and hyperlipidemia. Remnant-like lipoprotein particles cholesterol (RLP-C) are a known risk factor for cardiovascular events. The present study was performed to determine possible differences in fasting blood RLP-C levels between schizophrenic patients treated with risperidone as compared to olanzapine. Patients on olanzapine had significantly higher RLP-C levels than those on risperidone (p < 0.01). In olanzapine-treated patients there was no abnormality in fasting blood glucose levels, but fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) were elevated. RLP-C levels were significantly correlated with plasma triglyceride concentrations in both the olanzapine- (p < 0.01) and risperidone-treated patients (p < 0.01). The regression line slope was greater for the olanzapine group, suggesting a greater influence of olanzapine on RLP-C. There was a significant correlation between RLP-C and HOMA-IR in the risperidone group (p < 0.01) but not in the olanzapine group (p = 0.80). These results suggest that blood glucose monitoring may not be sufficient to detect metabolic disorder and that measurement of RLP-C might be helpful for the screening for metabolic disorders associated with olanzapine therapy.

Dopamine receptor D3 genotype association with greater acute positive symptom remission with olanzapine therapy in predominately caucasian patients with chronic schizophrenia or schizoaffective disorder

To test association of dopamine receptor D3 (DRD-3) gene polymorphisms with olanzapine response in genetic samples from a registration phase clinical trial. Eighty-eight acutely ill patients with schizophrenia or schizoaffective disorder were genotyped for ser-9-gly (rs6280) and 23 other polymorphisms within the DRD-3 gene. Allelic association of clinical response (mean baseline- to-endpoint reduction in Positive and Negative Syndrome Scale [PANSS] total and subscores) over 6 weeks of olanzapine treatment was assessed using repeated measures analysis of variance. Ser-9-gly genotypes were associated with differences in PANSS total score improvement from baseline to 6 weeks (p = 0.021). This association was most notable for improvement in positive symptoms (p = 0.0001), with patients with gly/gly genotype significantly more responsive. More patients with the gly/gly genotype had greater positive symptom remission (endpoint rating of minimal or none on all PANSS positive items, 39.1%) compared with patients with gly/ser and ser/ser genotypes (13.8%; p = 0.033). DRD-3 polymorphisms in disequilibrium with ser-9-gly were also significantly associated with greater positive symptom improvement (p = 0.0009-0.021), and one not in complete linkage disequilibrium, with lesser improvement (p = 0.027). Gly/gly DRD-3 genotype predicted statistically and clinically significantly better acute positive symptom reduction compared with other ser-9-gly genotypes in patients treated with olanzapine.

Cerebrospinal fluid d-serine and glycine concentrations are unaltered and unaffected by olanzapine therapy in male schizophrenic patients

N-Methyl d-aspartate (NMDA)-receptor hypofunction has been implicated in the pathophysiology of schizophrenia and d-serine and glycine add-on therapy to antipsychotics has shown beneficial effects in schizophrenic patients. Nevertheless, previous studies have not shown consistently altered d-serine concentrations in cerebrospinal fluid (CSF) of schizophrenic patients. To confirm and extend these results, CSF concentrations of both endogenous NMDA-receptor co-agonists d-serine and glycine and their common precursor l-serine were analyzed simultaneously in 17 healthy controls and 19 schizophrenic patients before and 6 weeks after daily olanzapine (10 mg) treatment. CSF d-serine, l-serine and glycine concentrations and their relative ratios were similar between schizophrenic patients and controls and no differences were observed before and after olanzapine therapy. Thus, the NMDA-receptor hypofunction hypothesis in schizophrenia is not explained by olanzapine therapy-dependent absolute or relative decreases in CSF d-serine and glycine concentrations in this series of male patients, thereby not providing convenient markers for the disorder.

Valproate-Induced Subclinical Hypothyroidism

Back to table of contents Previous article Next article LETTERFull AccessValproate-Induced Subclinical HypothyroidismPallavi Rao M.D.D.S., M.D.Shanker Madhav Natu M.Sc., Ph.D.Madhu Mati Goel M.B.B.S., M.D.Bashir Ali M.Sc., Ph.D.,Pallavi Rao M.D.D.S., M.D.Search for more papers by this authorShanker Madhav Natu M.Sc., Ph.D.Search for more papers by this authorMadhu Mati Goel M.B.B.S., M.D.Search for more papers by this authorBashir Ali M.Sc., Ph.D.Search for more papers by this author,Published Online:1 Jan 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Drug-induced hypothyroidism has been well established in the literature with drugs like lithium, iodine, and amiodarone. We report a rare case of subclinical hypothyroidism in a patient on long-term valproate therapy. A 30-year-old patient undergoing treatment for manic-depressive bipolar disorder presented with complaints of increasing fatigue and weakness. He was on sodium valproate and olanzapine therapy for 8 years before his clinical presentation. His laboratory findings revealed a raised thyrotropin (TSH) of 27.61 microIU/ml (normal range=4–7 microIU/ml) with normal T3 and T4, on two consecutive occasions. His liver function tests showed a raised SGPT (60U/liter). His renal function tests and basic hematological parameters were within normal limits. Subsequent tests for antithyroid antibodies were negative. There was no past history or family history of any thyroid disease. Subclinical hypothyroidism is manifested by raised TSH with normal T3 and T4 levels. The prevalence of subclinical hypothyroidism is approximately 14% and is more frequently observed in females. 1 The main causes of hypothyroidism are autoimmune disorders, inflammation, iodine deficiency, drugs, radio ablated thyroid gland, post surgical resection, and pituitary disorders. Patients with subclinical hypothyroidism may occasionally present with signs and symptoms of clinically apparent hypothyroidism, such as fatigue, weight gain, and dry skin. The association of hypothyroidism with drugs like lithium, amiodarone, and iodine is well established in the literature. Antiepileptic drugs, however, have been recently added to the list. Sodium valproate is commonly used in the treatment of epilepsy and bipolar disorder. It acts by destroying γ-aminobutyric acid (GABA) antagonist thereby increasing the levels of GABA, which is said to have an antimanic effect. The well-known side effects of valproate therapy are weight gain, dyspepsia, headache, and hepatotoxicity. Studies in children undergoing long-term valproate therapy have shown a significantly higher level of TSH compared to controls. 2 Higher levels of TSH, with normal T3 and T4, were also seen in girls undergoing valproate monotherapy. 3 Contradictory to this, some reports suggest that though antiepileptic drugs like carbamazepine and phenytoin have been found to induce hypothyroidism—due to their hepatic enzyme induction properties which lead to increased clearance of thyroid hormones—valproate did not seem to have the same effect on thyroid function as it was not a hepatic enzyme inducer. 4As our patient presented with excessive fatigue, we evaluated his thyroid function tests, which revealed a subclinical hypothyroid state. Increased SGPT levels noted in the patient may be due to hepatotoxic potential of valproate. The patient had no history of radioiodine therapy or any surgical procedure which might have accounted for this clinical state. The patient had negative antithyroid antibody screens ruling out autoimmune causes. As there was no evidence in the literature to support the role of olanzapine in induction of hypothyroidism, we attribute the hypothyroid state of our patient to long-term valproate therapy.This case report highlights the importance of routine thyroid function tests in patients undergoing long-term valproate therapy, which may lead to early detection of subclinical hypothyroid state and thereby prevent subsequent complications.King George Medical University, Lucknow, IndiaReferences1 . Díez JJ, Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 2004; 89:4890–4897Google Scholar2 . Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, et al: Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia 1999; 40:1761–1766Google Scholar3 . Vainionpaa LK, Mikkonen K, Rattya J, et al: Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication. Epilepsia 2004; 45:197–203Google Scholar4 . Isojarvi JI, Pakarinen AJ, Myllyla VV: Thyroid function with antiepileptic drugs. Epilepsia 1992; 33:142–148Google Scholar FiguresReferencesCited byDetailsCited BySevere fatigue due to valproate-induced hypothyroidism in a case of bipolar disorder5 September 2020 | Annals of General Psychiatry, Vol. 19, No. 1Effect of antiepileptic drugs on the thyroid gland in adult albino ratsThe Egyptian Journal of Histology, Vol. 38, No. 1 Volume 20Issue 1 Winter, 2008Pages 111-112 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008