Use of carbamazepine in psychiatric disorders

Use of carbamazepine for the treatment of psychiatric disorders is reviewed. Carbamazepine's mechanism of action may be related to inhibition of kindling (repeated subtherapeutic electrical stimulation) in the temporal lobe and limbic system. In most published studies, carbamazepine was useful in affective disorders, especially in patients with bipolar manic disorders. In controlled, double-blind studies in patients with primary affective or schizoaffective disorders, carbamazepine significantly decreased manic symptoms and showed some antidepressant effect. Synergistic effects have been observed when carbamazepine is used with lithium. Carbamazepine has been reported to decrease symptoms in patients with aggression, dyscontrol syndromes, schizophrenia, and alcohol withdrawal syndrome, but few of these studies have been controlled, comparative trials; carbamazepine may be useful in patients with these disorders who do not respond to conventional therapies. Beneficial effects of carbamazepine in psychiatric disorders are usually observed with doses of 400-1600 mg/day and serum concentrations of 8-12 micrograms/mL. Carbamazepine is useful alone or in combination with other agents for bipolar affective disorders, especially in patients who are intolerant of or unresponsive to lithium. Serum carbamazepine concentration, hematological profile, and serum electrolytes should be monitored carefully to minimize the risk of toxicity.     

New pharmacological approaches for the treatment of alcoholism

Pharmacological relapse prevention in alcoholism is a rather new clinical field with few drugs being available. Acamprosate, acting predominantly via glutamatergic pathways, and the opioid receptor antagonist naltrexone, were both shown to be efficient in improving rates for continuous abstinence, and not relapsing to heavy drinking in a number of clinical trials and meta-analyses. There are conflicting data on both drugs, especially for acamprosate, according to some recent US studies. However, overall, the evidence is good. Both drugs are approved in most European countries and the US. Efficacy data for disulfiram are mixed; it is a second-line medication compared with other drugs, and is probably most effective when used in a supervised setting. Recently, anticonvulsants including carbamazepine and topiramate have been discussed as possible anti-craving drugs, but there is still limited evidence for their efficacy. Although there is a significant comorbidity for alcoholism with affective disorder, anxiety and schizophrenia, relatively few controlled clinical trials have been performed in this area. Tricyclics have been found to be more effective than serotonin reuptake inhibitors in improving depressive symptoms in these patients.     

New pharmacological approaches for the treatment of alcoholism

Pharmacological relapse prevention in alcoholism is a rather new clinical field with few drugs being available. Acamprosate, acting predominantly via glutamatergic pathways, and the opioid receptor antagonist naltrexone, were both shown to be efficient in improving rates for continuous abstinence, and not relapsing to heavy drinking in a number of clinical trials and meta-analyses. There are conflicting data on both drugs, especially for acamprosate, according to some recent US studies. However, overall, the evidence is good. Both drugs are approved in most European countries and the US. Efficacy data for disulfiram are mixed; it is a second-line medication compared with other drugs, and is probably most effective when used in a supervised setting. Recently, anticonvulsants including carbamazepine and topiramate have been discussed as possible anti-craving drugs, but there is still limited evidence for their efficacy. Although there is a significant comorbidity for alcoholism with affective disorder, anxiety and schizophrenia, relatively few controlled clinical trials have been performed in this area. Tricyclics have been found to be more effective than serotonin reuptake inhibitors in improving depressive symptoms in these patients.     

Carbamazepine decreases antihypertensive effect of nilvadipine.

A 59-year-old male who had suffered from hypertension for 21 years was admitted because of manic and delusional symptoms. He was treated with 12 mg/day of haloperidol for psychotic symptoms and 8 mg/day of nilvadipine for hypertension. Due to insufficient effect of haloperidol on the patient's manic symptoms, carbamazepine was added to these medications. Abnormally high blood pressure was observed during carbamazepine coadministration, and it returned gradually to normal range after its discontinuation. Retrospective analyses revealed that the plasma concentrations of nilvadipine were undetectable during carbamazepine treatment. The clinical course and laboratory findings suggest that carbamazepine decreased the plasma concentration and hence the antihypertensive effect of nilvadipine probably via CYP3A induction. This interaction between nilvadipine and carbamazepine should be kept in mind when these drugs are administered concomitantly.     

Mood stabilizers increase prepulse inhibition in DBA/2NCrl mice

Rationale  Lithium and several antiepileptic drugs have mood-stabilizing effects in bipolar disorder and schizophrenia. Both disorders are characterized by deficits in prepulse inhibition (PPI) of the acoustic startle response. Objectives  Using the DBA/2 model of naturally low PPI, which is reliably increased by antipsychotics, five mood stabilizers in clinical use were tested to determine whether they would also increase PPI in this model. All drugs were administered intraperitoneally (i.p.) 30 min before testing. Results  Lithium chloride (30 mg/kg), topiramate (100 and 300 mg/kg), carbamazepine (30, 60, and 100 mg/kg), valproic acid (178 and 316 mg/kg), and lamotrigine (3, 10, and 30 mg/kg) increased percent PPI. The antiepileptic drugs carbamazepine, valproic acid, and lamotrigine at high doses also decreased no-stimulus amplitudes and increased startle amplitudes. At high doses of carbamazepine, valproic acid, and lamotrigine, increases in percent PPI were independent of the increases in startle amplitude. Conclusions  The demonstrated efficacy of five mood stabilizers in the DBA/2 model of naturally low PPI points to the translational value of this model in predicting therapeutic activity in schizophrenia and bipolar disorder of compounds with diverse mechanisms of action.     

A possible case of carbamazepine-induced pancreatitis

At least 25 different drugs have been implicated in drug-induced pancreatitis. For some drugs the evidence is strong, but for many a contradictory or incomplete association exists between their administration and the occurrence of pancreatitis. To our knowledge, carbamazepine has not been associated with pancreatitis. We report a case of a 73-year-old female on carbamazepine 200 mg bid for partial complex seizures who developed nausea, fatigue, anorexia, malaise, headache, and increased thirst. After carbamazepine discontinuation, the patient noted an almost immediate decrease in all symptoms. Her seizures are now treated successfully with phenytoin.     

Inhibition of D-amino acid oxidase activity by antipsychotic drugs evaluated by a fluorometric assay using D-kynurenine as substrate

A facile fluorometric assay using D-kynurenine as a substrate was utilized for evaluating the inhibition of D-amino acid oxidase (DAAO), which is one of the products of a susceptibility gene for schizophrenia, by commercial antipsychotic drugs, namely, chlorpromazine (CPZ), carbamazepine, sulpiride, quetiapine, and imipramine. CPZ inhibited DAAO (65.8 ± 13.2 μM, n = 3) as reported previously, and other drugs also inhibited DAAO activity. Among these, quetiapine had the smallest IC(50) value (19.5 ± 2.60 μM, n = 3). The proposed assay can be useful for the evaluation or screening of DAAO-inhibitory drugs.     

Potential drug targets and treatment of schizophrenia

Schizophrenia is one of the most prevalent chronic psychiatric disorders that affect 1% of the world’s population. Despite its societal burden, pathophysiology of schizophrenia remains poorly understood. Currently available drugs predominantly control positive symptoms, and often have no or poor control on negative and related cognitive symptoms, which strongly affect functional outcome in schizophrenia. The present article is an attempt to provide a critical review of recent hypothesis to understand pathophysiology of schizophrenia and to highlight exploitable molecular drug targets other than dopaminergic systems to treat and manage schizophrenia effectively.     

Efficacy and safety of novel antipsychotics: a critical review

Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.     

Combination of ziprasidone and clozapine in treatment-resistant schizophrenia

In cases of treatment-resistant schizophrenia the combined application of antipsychotic drugs often becomes necessary. Clozapine has been combined successfully with other atypical antipsychotic drugs such as risperidone or amisulpride in the past.We report the difficult treatment of a 28-year-old schizophrenic woman. Psychotic symptoms were found resistant to monotherapy with clozapine or ziprasidone. In contrast, combined application led to a marked improvement in both positive and negative symptoms of schizophrenia along with a decrease of side effects.The reported combination is a promising option in cases of treatment-resistant schizophrenia and should be further evaluated in prospective studies.     

The revised dopamine hypothesis of schizophrenia: evidence from pharmacological MRI studies with atypical antipsychotic medication

The revised dopamine (DA) hypothesis states that clinical symptoms of schizophrenia are caused by an imbalance of the DA system. In this article, we aim to review evidence for this hypothesis by evaluating functional magnetic resonance imaging studies in schizophrenia. Because atypical drugs are thought to have a normalizing effect on DA neurotransmission, we have focused on pharmacological MRI (PhMRI) studies that explore the effect of these drugs on prefrontal and striatal brain activity in schizophrenia patients. We encountered a total of 13 studies, most of which reported enhanced prefrontal activity associated with alleviation of negative symptoms and improvement of cognitive functions, following treatment with atypical antipsychotics. Besides increasing prefrontal cortex activity, atypical antipsychotics have also shown to be effective in the regulation of striatal functioning. The current PhMRI findings support the revised DA hypothesis of schizophrenia by confirming hypoactivity of the prefrontal cortex in schizophrenia and, following atypical antipsychotics, improvement of prefrontal and subcortical functions reflecting enhanced DA activity.     

Pharmacokinetics of aripiprazole and concomitant carbamazepine

The objective of this study was to assess the pharmacokinetics of aripiprazole when coadministered with carbamazepine using an open-label sequential treatment design in patients with schizophrenia or schizoaffective disorder. Nine male patients were enrolled and received aripiprazole monotherapy (30 mg once daily) for 14 days, after which aripiprazole steady-state pharmacokinetics were assessed. Subjects were then administered carbamazepine together with aripiprazole for 4 to 6 weeks. The dose of carbamazepine was titrated to produce a trough serum concentration within the range of 8 to 12 mg/L. Aripiprazole pharmacokinetics were then assessed in the presence of carbamazepine. Six patients completed the study as designed. Coadministration with carbamazepine decreased the values of mean peak plasma concentration and area under the plasma concentration-time curve of aripiprazole by 66% and 71%, respectively (P = 0.001 and 0.002, respectively). Similarly, coadministration with carbamazepine decreased the values of mean peak plasma concentration and area under the plasma concentration-time curve over the 24-hour dosing interval of the major active metabolite of aripiprazole, dehydroaripiprazole, by 68% and 69%, respectively (P < 0.001). Both aripiprazole and dehydroaripiprazole are substrates for the cytochrome P-450 3A4 enzyme which is known to be induced by carbamazepine dosed to steady state. Thus, therapeutic doses of carbamazepine had significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled (to 20-30 mg/d). Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from combination therapy, aripiprazole dose should then be reduced.     

Potential serotonergic agents for the treatment of schizophrenia

Introduction: For the last 30 years, drugs targeting serotonin receptors (5-HTR) have been intensively investigated in schizophrenia. New drugs targeting 5-HTRs are under development in patients with schizophrenia.

Areas covered: In this review, the authors describe the recent clinical trials for schizophrenia with selective serotonergic agents and provide an opinion on how the investigated drugs can help to fulfil current treatment needs. Clinical trials were found in US and EU clinical trial registries and in the medical literature. Relevant 5-HTR antagonists active in animal models of schizophrenia were also analysed.

Expert opinion: Antipsychotics reduce positive symptoms of schizophrenia (delusions, hallucinations and disordered thought), but have undesirable side effects. Moreover, satisfactory treatment of negative symptoms (apathy, poverty of speech, lack of interest in social interactions) and cognitive dysfunction is currently not available. The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine. Adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions. Selective 5-HT3R antagonists (ondansetron, tropisetron and granisetron) showed positive results on negative symptoms and/or cognitive impairments in phase II trials. Adjunctive ondansetron has now entered a phase III trial for such indications. Finally, 5-HTA5R and 5-HT7R antagonists have shown procognitive actions in animal models of schizophrenia. These novel serotonergic drugs seem promising for improving the current treatment of schizophrenia.     

Evolution of schizophrenia drugs: a focus on dopaminergic systems

Many of the drugs currently marketed for the treatment of schizophrenia are dopamine D2 receptor antagonists or partial agonists with or without mixed receptor pharmacology, and primarily treat the positive symptoms of schizophrenia. These drugs, depending on their pharmacological profile, have been categorized as typical (with low or no serotonergic component) and atypical (with a high serotonergic, 5-HT2A and 5-HT1A component) antipsychotics. Atypical antipsychotics have increased tolerability compared with typical antipsychotics, particularly against extrapyramidal side effects which are caused by D2 receptor antagonism, and an increased efficacy for the treatment of the negative symptoms associated with schizophrenia. However, over the course of treatment, adverse effects such as weight gain, metabolic disorders, QT prolongation and sexual dysfunction have been observed, and thus current research efforts are being directed to the identification of new antipsychotics that have better tolerability and efficacy against the positive and negative symptoms of schizophrenia.     

The new antipsychotics--some pharmacological aspects of their problems and potential

The drug treatment of schizophrenia still offers many challenges, despite the efficacy of the classical antipsychotics. Although the more recently introduced drugs demonstrate a diminished incidence of certain side effects, notably extrapyramidal motor symptoms, it is clear that they do not adequately address all symptoms of the disease. In addition, weight gain remains a major problem following treatment with many older and newer antipsychotic drugs. Nevertheless, some progress has been made towards ameliorating negative, depressive and cognitive features of schizophrenia. The newer antipsychotics show differential effects against these and other symptoms and thus their pharmacological profiles provide us with clues as to the receptor mechanisms underlying their therapeutic and side effects.     

Gamma synchrony: towards a translational biomarker for the treatment-resistant symptoms of schizophrenia

The lack of efficacy for antipsychotics with respect to negative symptoms and cognitive deficits is a significant obstacle for the treatment of schizophrenia. Developing new drugs to target these symptoms requires appropriate neural biomarkers that can be investigated in model organisms, be used to track treatment response, and provide insight into pathophysiological disease mechanisms. A growing body of evidence indicates that neural oscillations in the gamma frequency range (30-80 Hz) are disturbed in schizophrenia. Gamma synchrony has been shown to mediate a host of sensory and cognitive functions, including perceptual encoding, selective attention, salience, and working memory - neurocognitive processes that are dysfunctional in schizophrenia and largely refractory to treatment. This review summarizes the current state of clinical literature with respect to gamma-band responses (GBRs) in schizophrenia, focusing on resting and auditory paradigms. Next, preclinical studies of schizophrenia that have investigated gamma-band activity are reviewed to gain insight into neural mechanisms associated with these deficits. We conclude that abnormalities in gamma synchrony are ubiquitous in schizophrenia and likely reflect an elevation in baseline cortical gamma synchrony ('noise') coupled with reduced stimulus-evoked GBRs ('signal'). Such a model likely reflects hippocampal and cortical dysfunction, as well as reduced glutamatergic signaling with downstream GABAergic deficits, but is probably less influenced by dopaminergic abnormalities implicated in schizophrenia. Finally, we propose that analogous signal-to-noise deficits in the flow of cortical information in preclinical models are useful targets for the development of new drugs that target the treatment-resistant symptoms of schizophrenia.     

Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection

Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.     

Omega-3 fatty acids as a psychotherapeutic agent for a pregnant schizophrenic patient.

Because of the potential adverse events and teratogenesis of antipsychotic drugs, it is important to find a safe and effective treatment for pregnant women with severe mental illness. The membrane hypothesis of schizophrenia provides a rationale to treat symptoms of schizophrenia with omega-3 PUFAs. We report a 30-year-old married woman with chronic schizophrenia, who experienced an episode of acute exacerbation of psychotic symptoms during pregnancy. After entering into an open trial of omega-3 PUFAs monotherapy, she showed a dramatic improvement in both positive and negative symptoms of schizophrenia and a significant increase of omega-3 PUFA composition in erythrocyte membrane. There were no adverse effects in this treatment. Thus, omega-3 PUFAs could be both beneficial and therapeutic to pregnant schizophrenic women.     

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.     

Old and new approaches to drug treatment of schizophrenia

More than 30 years have passed since the introduction of effective antipsychotic drugs. These drugs have revolutionized both the treatment of patients with schizophrenia and the thinking about the nature of this disorder. During this time, technical improvements have widened the scope of usefulness of these agents. However, no newer drug has been more effective overall than was the first, chlorpromazine. In addition, many patients respond poorly or not at all to drug therapy; others find the side effects of present drugs unbearable. Tardive dyskinesia and tardive psychosis are developments following long-term treatment that may have serious import. Many questions about drug therapy remain unanswered. Which drug? How much? Intermittent or continual maintenance therapy? What new approaches to treatment can be considered? Atypical neuroleptics that may specifically bind to receptors in the mesolimbic system constitute the major thrust of current drug development. Interest in benzodiazepines as adjunctive agents have revived. The role of propranolol remains uncertain; it seems more to be an adjunctive treatment. Lithium and carbamazepine may be suitable adjuncts for patients who are otherwise refractory to treatment. Use of neuropeptides was greeted with initial enthusiasm, which is rapidly waning as more experience develops. New approaches to drug treatment for schizophrenia are desperately needed.