Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Weight gain associated with psychotropic drugs

Weight gain is a common adverse effect of psychotropic drugs. Clinically significant weight gain puts the patient at risk for coronary heart disease, hypertension, Type II diabetes, dyslipidaemia and cancer, and can lead to non-compliance, with the probability of relapse and subsequent (re)hospitalisation. This review focuses on specific drug classes such as antipsychotics, antidepressants, mood stabilisers and anxiolytics that have a propensity to induce clinically significant weight gain. Patients should be informed of potential drug-induced weight gain and instructed in the importance of weight management techniques (e.g., proper nutrition, physical exercise, behaviour modification). Individual patient-risk profiles should also be assessed. To ensure adherence to treatment, a proactive physician-patient relationship is essential. Patient compliance and quality-of-life issues are addressed. For appropriate medication selection, the clinician should consider the weight gain potential of various psychotropic agents.     

Psychotropic drugs,cardiac arrhythmia,and sudden death

A variety of drugs targeted towards the central nervous system are associated with cardiac side effects, some of which are linked with reports of arrhythmia and sudden death. Some psychotropic drugs, particularly tricyclic antidepressants (TCAs) and antipsychotic agents, are correlated with iatrogenic prolongation of the QT interval of the electrocardiogram (ECG). In turn, this is associated with the arrhythmia (TdP). This review discusses the association between psychotropic agents, arrhythmia and sudden death and, focusing on TCAs and antipsychotics, considers their range of cellular actions on the heart; potentially pro-arrhythmic interactions between psychotropic and other medications are also considered. At the cellular level TCAs, such as imipramine and amitriptyline, and antipsychotics, such as thioridazine, are associated with inhibition of potassium channels encoded by In many cases this cellular action correlates with ECG changes and a risk of TdP. However, not all psychotropic agents that inhibit HERG at the cellular level are associated equally with QT prolongation in patients, and the potential for QT prolongation is not always equally correlated with TdP. Differences in risk between classes of psychotropic drugs, and between individual drugs within a class, may result from additional cellular effects of particular agents, which may influence the consequent effects of inhibition of repolarizing potassium current.     

Clinically significant drug interactions with antidepressants in the elderly

Pharmacological treatment of depression in old age is associated with an increased risk of adverse pharmacokinetic and pharmacodynamic drug interactions. Elderly patients may have multiple disease states and, therefore, may require a variety of other drugs. In addition to polypharmacy, other factors such as age-related physiological changes, diseases, genetic constitution and diet may alter drug response and, therefore, predispose elderly patients to adverse effects and drug interactions. Antidepressant drugs currently available differ in their potential for drug interactions. In general, older compounds, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have a higher potential for interactions than newer compounds, such as selective serotonin reuptake inhibitors (SSRIs) and other relatively novel agents with a more specific mechanism of action. In particular, TCAs and MAOIs are associated with clinically significant pharmacodynamic interactions with many medications frequently prescribed to elderly patients. Moreover, TCAs may be susceptible to pharmacokinetic interactions when given in combination with inhibitors or inducers of the cytochrome P450 (CYP) isoenzymes involved in their metabolism. Because of a more selective mechanism of action, newer antidepressants have a low potential for pharmacodynamic drug interactions. However, the possibility of the serotonin syndrome should be taken into account when drugs affecting serotonergic transmission, such as SSRIs, venlafaxine or nefazodone, are coadministered with other serotonergic agents. Newer agents have a differential potential for pharmacokinetic interactions because of their selective effects on CYP isoenzymes. Within the group of SSRIs, fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine predominantly affects CYP1A2 and CYP2C19 activity. Therefore, these agents should be closely monitored or avoided in elderly patients treated with substrates of these isoforms, especially those with a narrow therapeutic index. On the other hand, citalopram and sertraline have a low inhibitory activity on different drug metabolising enzymes and appear particularly suitable in an elderly population. Among other newer antidepressants, nefazodone is a potent inhibitor of CYP3A4 and its combination with substrates of this isoform should be avoided.     

Metabolic drug interactions with newer antipsychotics: a comparative review

Newer antipsychotics introduced in clinical practice in recent years include clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and amisulpride. These agents are subject to drug-drug interactions with other psychotropic agents or with medications used in the treatment of concomitant physical illnesses. Most pharmacokinetic interactions with newer antipsychotics occur at the metabolic level and usually involve changes in the activity of the major drug-metabolizing enzymes involved in their biotransformation, i.e. the cytochrome P450 (CYP) monooxygenases and/or uridine diphosphate-glucuronosyltransferases (UGT). Clozapine is metabolized primarily by CYP1A2, with additional contribution by other CYP isoforms. Risperidone is metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4. Olanzapine undergoes both direct conjugation and CYP1A2-mediated oxidation. Quetiapine is metabolized by CYP3A4, while sertindole and aripiprazole are metabolized by CYP2D6 and CYP3A4. Ziprasidone pathways include aldehyde oxidase-mediated reduction and CYP3A4-mediated oxidation. Amisulpride is primarily excreted in the urine and undergoes relatively little metabolism. While novel antipsychotics are unlikely to interfere with the elimination of other drugs, co-administration of inhibitors or inducers of the major enzymes responsible for their metabolism may modify their plasma concentrations, leading to potentially significant effects. Most documented metabolic interactions involve antidepressant and anti-epileptic drugs. Of a particular clinical significance is the interaction between fluvoxamine, a potent CYP1A2 inhibitor, and clozapine. Differences in the interaction potential among the novel antipsychotics currently available may be predicted based on their metabolic pathways. The clinical relevance of these interactions should be interpreted in relation to the relative width of their therapeutic index. Avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and, possibly, plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving newer antipsychotics.     

Interactions between psychotropics, anaesthetics and electroconvulsive therapy: implications for drug choice and patient management

Despite many predictions that electroconvulsive therapy (ECT) would be replaced by pharmacotherapy, ECT has remained an invaluable adjunct in the management of severe psychiatric disease. Both pharmacotherapy and ECT continue to be used extensively, and will frequently be administered concurrently. The majority of patients requiring ECT will need anaesthesia; therefore, interactions could conceivably occur between the psychotropic drugs, ECT and the anaesthetic agents utilised. In managing an anaesthetic for ECT the effects of the anaesthetic agents and other medications on seizure intensity are important determinants influencing outcome. With regard to the antidepressants, tricyclic antidepressants (TCAs) and ECT can be combined safely and beneficially. More care is required when ECT is administered in the setting of a monoamine oxidase inhibitor (MAOI), especially the older irreversible varieties and in patients recently placed on MAOI therapy. Of the anticonvulsants and mood stabilisers, lithium and ECT given concurrently add significant risk of delirium and/or organic syndromes developing. Possible concerns with valproate, carbamazepine, lamotrigine, gabapentin and topiramate are that they may inhibit seizure activity. Additionally, carbamazepine may prolong the action of suxamethonium (succinylcholine). The combination of antipsychotics and ECT is well tolerated, and may in fact be beneficial. As regards the anxiolytics, benzodiazepines have anticonvulsant properties that might interfere with the therapeutic efficacy of ECT. CNS stimulants on the other hand may prolong seizures as well as produce dysrhythmias and elevate blood pressure. Calcium channel antagonists should be used with great care to avoid significant cardiovascular depression. The anaesthesiologist should therefore remain vigilant at all times, as untoward responses during ECT might occur suddenly due to interactions between psychotropics, anaesthetic agents and/or ECT.     

Effects of psychotropic drugs on seizure threshold.

Psychotropic drugs, especially antidepressants and antipsychotics, may give rise to some concern in clinical practice because of their known ability to reduce seizure threshold and to provoke epileptic seizures. Although the phenomenon has been described with almost all the available compounds, neither its real magnitude nor the seizurogenic potential of individual drugs have been clearly established so far. In large investigations, seizure incidence rates have been reported to range from approximately 0.1 to approximately 1.5% in patients treated with therapeutic doses of most commonly used antidepressants and antipsychotics (incidence of the first unprovoked seizure in the general population is 0.07 to 0.09%). In patients who have taken an overdose, the seizure risk rises markedly, achieving values of approximately 4 to approximately 30%. This large variability, probably due to methodological differences among studies, makes data confusing and difficult to interpret. Agreement, however, converges on the following: seizures triggered by psychotropic drugs are a dose-dependent adverse effect; maprotiline and clomipramine among antidepressants and chlorpromazine and clozapine among antipsychotics that have a relatively high seizurogenic potential; phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, venlafaxine and trazodone among antidepressants and fluphenazine, haloperidol, pimozide and risperidone among antipsychotics that exhibit a relatively low risk. Apart from drug-related factors, seizure precipitation during psychotropic drug medication is greatly influenced by the individual's inherited seizure threshold and, particularly, by the presence of seizurogenic conditions (such as history of epilepsy, brain damage, etc.). Pending identification of compounds with less or no effect on seizure threshold and formulation of definite therapeutic guidelines especially for patients at risk for seizures, the problem may be minimised through careful evaluation of the possible presence of seizurogenic conditions and simplification of the therapeutic scheme (low starting doses/slow dose escalation, maintenance of the minimal effective dose, avoidance of complex drug combinations, etc.). Although there is sufficient evidence that psychotropic drugs may lower seizure threshold, published literature data have also suggested that an appropriate psychotropic therapy may not only improve the mental state in patients with epilepsy, but also exert antiepileptic effects through a specific action. Further scientific research is warranted to clarify all aspects characterising the complex link between seizure threshold and psychotropic drugs.     

Psychotropic medications and the risk of fracture: a meta-analysis.

BACKGROUND: Older adults throughout the developed world are at significant risk of osteoporotic fractures. Many studies have examined the relationship between the use of psychotropic medications and the risk of fractures, but these studies have reported conflicting results. PURPOSE: To resolve discrepancies, we carried out a meta-analysis to assess the risk of fractures among users of several classes of psychotropic drugs. DATA SOURCES: We retrieved studies published in any language by systematically searching MEDLINE, LILACS, EMBASE and ISI Proceedings databases and by manually examining the bibliographies of the articles retrieved electronically as well as those of recent reviews. STUDY SELECTION: We included 98 cohort and case-control studies, published in 46 different articles, that reported relative risk (RR) estimates and confidence intervals (CIs) or sufficient data to calculate these values. DATA SYNTHESIS: Study-specific RRs were weighted by the inverse of their variance to obtain fixed- and random effects pooled estimates. The random effects RR of fractures was 1.34 (95% CI 1.24, 1.45) for benzodiazepines (23 studies), 1.60 (95% CI 1.38, 1.86) for antidepressants (16 studies), 1.54 (95% CI 1.24, 1.93) for non-barbiturate antiepileptic drugs (13 studies), 2.17 (95% CI 1.35, 3.50) for barbiturate antiepileptic drugs (five studies), 1.59 (1.27, 1.98) for antipsychotics (12 studies), 1.15 (95% CI 0.94, 1.39) for hypnotics (13 studies) and 1.38 (95% CI 1.15, 1.66) for opioids (six studies). For non-specified psychotropic drugs (10 studies), the pooled RR was 1.48 (95% CI 1.41, 1.59). LIMITATIONS: Main concerns were the potential for residual confounding and for publication bias. CONCLUSION: Globally, the increase in the risk of fractures among psychotropic drug users is moderate. Further research is needed, especially to examine high-risk populations and newer medications. Future studies should be prospective and emphasise control of confounding bias.     

老年精神障碍患者精神药物临床使用分析

目的:了解老年精神障碍患者精神药物临床使用情况。方法:收集肇庆市第三人民医院2008年1月1日-2008年12月31日出院,年龄60a或以上老年住院精神障碍患者的病历175份,采用限定日剂量(DDD)和药物利用指数(DUI)对精神药物的使用进行回顾性分析。结果:非典型抗精神病药利培酮的使用频率居首位,其次为奋乃静;抗抑郁药中舍曲林居首位,其次为帕罗西汀;在联合用药方面,抗精神病药与苯二氮艹卓类药物、抗抑郁药与苯二氮卓艹类药物和情感稳定剂、抗精神病药与抗抑郁药联用较多。在使用的33种精神药物中除舒必利、丙戊酸钠、阿普唑仑、三唑仑外,其余药物的DUI均≤1.0。结论:我院对老年精神障碍患者精神药物的使用基本合理。非典型抗精神病药、新型抗抑郁药的使用越来越多。     

Pharmacological aspects of the treatment of conduct disorder in children and adolescents

In recent years, the rates of psychosocial disorders in children and adolescents have increased, with behavioural manifestations of conduct disorder being one of the most common reasons for referrals to community psychiatrists. Childhood conduct problems are associated with a variety of psychiatric disorders in adult life that extend beyond antisocial behaviour. An increased awareness of the costs of conduct disorder to individuals, families and society has led to advancements in the pharmacological and nonpharmacological therapeutic modalities for this disorder. Despite this, patients with conduct disorder are difficult to treat as the patterns of maladaptive behaviours they exhibit are diverse and can vary as a function of age and sex. A multidisciplinary approach to the treatment of conduct disorder, which includes behavioural parent training, interpersonal skills training, family therapy and the use of psychotropic agents targeted at a particular cluster of symptoms, can increase the overall effectiveness of each of the applied interventions. Aggression, hyperactivity, impulsivity and mood symptoms are the most sensitive proximal targets. Evidence suggests that antipsychotics, antidepressants, mood stabilisers, antiepileptic drugs, stimulants and adrenergic drugs can be well tolerated and effective therapeutic options for individuals with conduct disorder and comorbid psychiatric conditions. However, the most successful therapeutic outcomes are likely to be achieved by combining the current advances in psychopharmacology with behavioural and psychosocial interventions, aimed at modifying the excessive patterns of maladaptive behaviours observed in conduct disorder.     

Weight gain associated with psychotropic drugs

Weight gain is a common adverse effect of psychotropic drugs. Clinically significant weight gain puts the patient at risk for coronary heart disease, hypertension, Type II diabetes, dyslipidaemia and cancer, and can lead to non-compliance, with the probability of relapse and subsequent (re)hospitalization. This review focuses on specific drug classes such as antipsychotics, antidepressants, mood stabilizers and anxiolytics that have a propensity to induce clinically significant weight gain. Patients should be informed of potential drug-induced weight gain and instructed in the importance of weight management techniques (e.g., proper nutrition, physical exercise, behaviour modification). Individual patient-risk profiles should also be assessed. To ensure adherence to treatment, a proactive physician-patient relationship is essential. Patient compliance and quality-of-life issues are addressed. For appropriate medication selection, the clinician should consider the weight gain potential of various psychotropic agents.     

Cytochrome P450 polymorphisms and response to antipsychotic therapy

Antipsychotic drugs are used for the treatment of schizophrenia and other related psychotic disorders. The antipsychotics currently available include older or classical compounds and newer or atypical agents. Most antipsychotic drugs are highly lipophilic compounds and undergo extensive metabolism by cytochrome P450 (CYP) enzymes in order to be excreted. There is a wide interindividual variability in the biotransformation of antipsychotic drugs, resulting in pronounced differences in steady-state plasma concentrations and, possibly, in therapeutic and toxic effects, during treatment with fixed doses. Many classical and some newer antipsychotics are metabolized to a significant extent by the polymorphic CYP2D6, which shows large interindividual variation in activity. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and occurrence of drug interactions. No relationship between CYP2D6 genotype or activity and therapeutic effects of classical antipsychotic drugs has been found in the few studies performed. On the other hand, some investigations suggest that poor metabolizers (PMs) of CYP2D6 would be more prone to over-sedation and, possibly, Parkinsonism during treatment with classical antipsychotics, while other studies, mostly retrospective, have been negative or inconclusive. For the newer antipsychotics, such data are lacking. To date, CYP2D6 phenotyping and genotyping appear, therefore, to be clinically useful for dose predicting only in special cases and for a limited number of antipsychotics, while their usefulness in predicting clinical effects must be further explored.     

Clinically important drug interactions with zopiclone,zolpidem and zaleplon

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.     

Treating mood disorders during pregnancy: safety considerations.

Mood disorders in pregnancy may have a negative effect on self care and pregnancy outcome that affects the mother directly and the child indirectly. Thus, some women may require pharmacological treatment. Pharmacotherapy of mood disorders during pregnancy implies specific considerations.This paper presents an updated review of available studies on the treatment of mood disorders and present knowledge on teratogenicity, neonatal effects and long-term neurobehavioural effects for the different psychotropic drugs, including treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), other antidepressants, benzodiazepines, lithium, carbamazepine/valproic acid, lamotrigine and novel antipsychotics. However, the existing knowledge on the use of antidepressants and mood stabilising agents during pregnancy is hampered by a lack of results from randomised controlled trials.SSRIs and TCAs have not been associated with an increased risk of major malformations, but poor neonatal adaptation has been described. Benzodiazepines used in the first trimester have been associated with orofacial clefts. Mood stabilisers such as lithium, carbamazepine and valproic acid (sodium valproate) are associated with an increased risk of fetal malformations. Both benzodiazepines and lithium may cause adaptation problems in the newborn. In utero exposure to novel antipsychotics has not been associated with congenital malformations; however, the data are still limited. The knowledge about long-term neurobehavioural effects in the offspring is still limited for all agents and requires further investigation. Possible adverse effects of fetal exposure must be balanced against the adverse effects of an untreated maternal mood disorder.     

Clinical features, pathogenesis and management of drug-induced seizures

Many classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium salts, neuroleptics, antihistamines (H1-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, non-steroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article offers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and beta-lactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal.     

Clinically significant drug interactions with newer antidepressants

After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications. Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations.     

Psychotropic drugs in the treatment of obesity: what promise?

Obesity is a chronic and highly prevalent medical condition associated with increased risk for the development of numerous and sometimes fatal diseases. Despite its severity, there are few anti-obesity agents available on the market. Although psychotropic agents are not approved for the treatment of obesity, they have been used by clinicians as a therapeutic tool in daily clinical practice. The purpose of this article is to review the rationale, as well as the evidence, for the potential use of these agents in obesity treatment. Evidence for the efficacy of psychotropic agents in obesity treatment comes from different sources. The first type of evidence is weight loss observed with treatment in clinical trials of patients with neuropsychiatric syndromes (e.g. mood disorders, epilepsy). A recent example of such findings is the weight reduction reported in clinical trials involving obese patients with binge eating disorder. While randomised, controlled trials specifically designed to investigate the weight loss properties of psychotropic agents in obese patients are the most appropriate source of evidence of anti-obesity action, such trials remain scarce. The most studied psychotropic agents in obesity trials are drugs used in the treatment of mood disorders, i.e. mainly antidepressants and antiepileptics. SSRIs (e.g. fluoxetine, sertraline and fluvoxamine) were amongst the first psychotropic agents investigated in the treatment of obesity. Additional data have also been published for other antidepressants (e.g. venlafaxine, citalopram and bupropion) and antiepileptics (e.g. topiramate and zonisamide). Based on the available data for the efficacy of psychotropic agents in obesity and other related conditions, SSRIs may be considered for the management of certain subgroups of obese individuals with comorbid conditions such as depression, binge eating disorder and type 2 diabetes mellitus. In addition, some newer agents, such as bupropion, topiramate and zonisamide, appear to be promising candidates for selective use in the treatment of obesity. However, further studies are needed to define their possible role as new pharmacological options in the treatment of obesity.     

Pharmacokinetics of mood stabilizers and new anticonvulsants

Mechanisms of action, efficacy spectra, pharmacokinetics, and adverse effects differentiate the mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA). Lithium, which has a low therapeutic index, is excreted through the kidneys, resulting in renally mediated, but not hepatically mediated, drug-drug interactions. CBZ also has a low therapeutic index and is metabolized primarily by a single isoform (CYP3A3/4). It has an active epoxide metabolite, is susceptible to CYP3A3/4 or epoxide hydrolase inhibitors, and is able to induce drug metabolism (both via cytochrome P450 oxidation and conjugation). CBZ thus has multiple problematic drug-drug interactions. In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, and it is less susceptible to pharmacokinetic drug interactions. Still, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of certain medications by displacing them from plasma proteins. The newer anticonvulsants lamotrigine, topiramate, and tiagabine have different, generally less problematic, hepatically mediated drug-drug interactions. Gabapentin, which is renally excreted, lacks hepatic drug-drug interactions, though bioavailability may be reduced at higher doses. Recently approved anticonvulsants, including oxcarbazepine, zonisamide, and levetiracetam, may have improved pharmacokinetic profiles compared to older agents. Novel psychotropic effects of these drugs may also be demonstrated, based on their mechanisms of action and preliminary clinical data.     

Drug-use evaluation programs for psychotropic medications

Drug-use evaluation (DUE) programs for psychotropic medications at a state-operated mental health center are described. DUE programs were developed at Western Missouri Mental Health Center to monitor prescribing of medications in the hospital and ambulatory-care settings. DUE criteria were developed for all major groups of psychotropic medications: antipsychotics, antidepressants, antianxiety and hypnotic agents, lithium, and antiparkinsonian drugs. The criteria appear on special forms developed for the programs; pharmacists use these forms to evaluate every medication order for inpatients and every 50th medication order for ambulatory-care patients. Physicians are alerted to noncompliant prescribing practices by memorandum, oral consultation, or both. In 3204 inpatient DUEs conducted from July 1986 to December 1988, orders for antiparkinsonian drugs showed the poorest compliance with DUE criteria. In both the hospital and ambulatory-care settings, antiparkinsonian agents required the most follow-up. The overall compliance rate for inpatient DUEs was 84%; for ambulatory-care DUEs, the compliance rate was 64%. As a result of the ambulatory-care DUE program, basic laboratory studies and dyskinesia rating scales are being ordered on a more timely basis. These DUE programs have increased pharmacist monitoring of patient care and improved documentation of medication use.