The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics

There has been growing concern about the potential iatrogenic effects of several newer psychotropic drugs on reproductive health safety in women. Areas of particular concern in this regard include (1) controversies about a potential association between the use of valproate and development of polycystic ovary syndrome (PCOS), (2) the safety of use of newer psychotropic medications during pregnancy, and (3) safety issues with these medications in women while breastfeeding. This review summarizes current information about each of these areas. In particular, existing data suggest that (1) PCOS very likely represents a complex neuroendocrine disorder with multiple determinants; (2) menstrual irregularities may be a frequently seen phenomenon in women with bipolar illness, at least partially independent of psychotropic drug therapy; (3) potential central nervous system teratogenicity remains substantial during first-trimester exposure to valproate or carbamazepine; (4) with newer agents used for bipolar disorder and schizophrenia, safety data during pregnancy, while not definitive, are most abundant with olanzapine and with lamotrigine; relatively less is known about systematic pregnancy outcomes with other atypical antipsychotics or newer anticonvulsants; and (5) risks for neonatal safety during lactation continue to appear substantial with lithium, are of potential concern with lamotrigine and clozapine, are quite likely minimal with valproate or carbamazepine, and are indeterminate with most other new anticonvulsants or atypical antipsychotics. Recommendations are presented for clinical management in each of these instances.     

Acute akathisia and sodium valproate

Akathisia is a common and distressing side-effect of a number of psychotropic drugs, including neuroleptic medication. We report the case of a 38-year-old woman who suffers from bipolar affective disorder and developed acute akathisia following the introduction of sodium valproate as a mood stabilizer. The medication regimen at the onset of her akathisia is described and discussed with particular reference to the aetiology of her akathisia. It is not possible to say with certainty if her acute akathisia developed as a sole consequence of sodium valproate treatment or as a consequence of a possible synergistic effect of her other psychotropic medication, but a sodium-valproate-induced functional dopaminergic antagonism mediating her acute akathisia appears likely.     

Psychotropic drug interactions with valproate

Valproate is a well-established anticonvulsant that is increasingly being employed, often in combination with other psychotropics, for its mood-stabilizing properties. This compound is metabolized by conjugation, beta-oxidation, and cytochrome P450 oxidation (CYP2C9, CYP2C19, and CYP2A6) and also acts as a broad-spectrum inhibitor of a variety of hepatic enzymes including glucoronyltransferase, epoxide hydrolase, and the CYP2C enzymes. In addition, it exhibits saturable protein binding and competes with many drugs for protein binding sites. It is therefore not surprising that valproate has been noted to interact with psychotropic medications of all classes. This article provides an overview of the noted pharmacokinetic psychotropic interactions with valproate, with a particular focus on the mechanisms of these interactions and potential clinical consequences.     

Long-term topiramate treatment of psychotropic drug-induced weight gain: a retrospective chart review

OBJECTIVE: The objective of this study was to determine the efficacy and tolerability of long-term topiramate treatment of psychotropic drug-induced weight gain. METHOD: We conducted a retrospective review of the charts of patients treated with add-on topiramate in order to control weight gain induced by psychotropic drugs (antipsychotic drugs, lithium or valproate). RESULTS: The case series consisted of 100 patients. The mean final dose of topiramate was 186.8+/-138.3 mg/day, whereas the median dose was 200 mg/day for a total treatment duration of 41+/-38 weeks. Adverse events led to topiramate discontinuation in 22% of the sample. A significant reduction in body mass index was observed between the first and last measures, from 29.7+/-3.6 to 28+/-3.3 (t=5.82, P<.0005). The reduction in body mass index was greater in patients treated with antipsychotic drugs than in those treated with lithium or valproate alone. No difference was found between subjects with and those without comorbid active substance abuse or dependence. CONCLUSIONS: In this retrospective case series, topiramate was found to be effective in reversing weight gain associated with antipsychotic drugs, lithium or valproate. Tolerability of topiramate was an issue in some patients.     

Use of sodium valproate in violent and aggressive behaviors: a critical review

BACKGROUND: Valproate was initially introduced as an antiepileptic agent in 1967, but has been used over the years to treat a variety of psychiatric disorders. Its use in the treatment of patients exhibiting aggressive and violent behaviors has been reported in the literature as far back as 1988. However, these reports are uncontrolled, which is in marked contrast to the actual wide and established use of valproate for the treatment of aggressive behaviors. The aim of this report is to critically review the available data on valproate's use in nonbipolar patients with aggressive and violent behaviors. DATA SOURCES: The MEDLINE and PsycLIT databases were searched for all reports published from 1987-1998 containing the keywords valproate, the names of all commercial preparations, aggression, and violence. STUDY FINDINGS: Seventeen reports with a total of 164 patients were located. Ten of these were case reports with a total of 31 patients. Three were retrospective chart reviews with 83 patients, and 3 were open-label prospective studies with a total of 34 patients. No double-blind, placebo-controlled study could be found. An overall response rate of 77.1% was calculated when response was defined as a 50% reduction of target behavior. Most frequent diagnoses recorded were dementia, organic brain syndromes, and mental retardation. The antiaggressive response usually occurred in conjunction with other psychotropic medication. The dose and plasma valproate level required for response appeared to be the same as in the treatment of seizure disorders. DISCUSSION: While valproate's general antiaggressive effect is promising, in the absence of controlled data, conclusions are limited at this time. Specific recommendations for study design are given to obtain interpretable data for this indication.     

Clinical Correlates of Response to Valproate in Geriatric Inpatients

The efficacy of valproate for the management of adults with bipolar disorder has been repeatedly demonstrated in several studies. Patients with mixed states, rapid cycling, and EEG abnormalities have been shown to respond favorably to valproate. Valproate is also being increasingly used in disorders with aggressive or agitated features, such as the behavioral disorders of dementia; yet, few studies have documented the utility of valproate in geriatric patients. The need to document safe and effective pharmacologic agents to treat geriatric mood and behavioral disorders continues to increase with the growing elderly population. We conducted a retrospective study of the use of valproate in patients consecutively hospitalized over a 5-year period on a psychiatric unit. Thirty-nine patients over age 60 were identified and then categorized into non-, partial, and full responders based on Clinical Global Impression ratings. Information on diagnosis, age, valproate dose and serum concentration, psychiatric symptoms, medical comorbidity, concurrent psychotropic medications, and side effects was collected. Results suggest that responders to valproate (full or partial) over the age of 60 years were more likely to be female, younger, carry a diagnosis of bipolar disorder, and achieve higher serum valproate concentrations. Full responders had fewer psychotic symptoms but usually displayed manic symptoms. The date of this study suggests the need for controlled clinical trials to clarify the utility and clinical predictors of response to valproate in the geriatric population.     

A pilot study of loading versus titration of valproate in the treatment of acute mania

Objective:  This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania.
Method:  Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n=5; mean age=33.4) or slower titration dose (10 mg/kg/day; n=6, mean age=30.6) of valproate for 7 days without other psychotropic agents, with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale.
Results:  The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines.
Conclusion:  This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.     

Psychopharmacological neuroprotection in neurodegenerative diseases, part III: criteria-based assessment: a report of the ANPA committee on research

Neuroprotective therapies for neurodegenerative diseases (NDDs) have proven elusive. The established psychotropic agents commonly used to treat the neuropsychiatric manifestations of NDDs are potential neuroprotective therapies, and neuropsychiatrists and others may benefit from a knowledge of the neuroprotective properties of these medications. This report identifies FDA-approved, first-line psychotropic drugs affecting intracellular mechanisms and meriting disease-modifying clinical trials in NDDs. The authors evaluated evidence for neuroprotection according to 1) preclinical; and 2) clinical criteria. Despite low-to-moderate preclinical evidence scores and scant clinical evidence, the most promising investigative priorities are 1) lithium and paroxetine in Alzheimer's disease (AD); 2) lithium in tauopathies (frontotemporal lobar degeneration [FTLD], FTDP-17); 3) lithium-plus-valproate in AD and amyotrophic lateral sclerosis; 4) pramipexole and valproate in Parkinson's disease; 5) amantadine and buspirone in multiple system atrophy; and 6) antidepressants in Huntington's disease. Preliminary clinical results signal caution regarding olanzapine use in AD and poor tolerability of lithium in progressive supranuclear palsy and corticobasal degeneration. These preliminary findings can lead to further clinical drug trials on the use of these well-known medications, not only for their psychotropic effects, but also for neuroprotection in NDDs.     

Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents

OBJECTIVE: Despite increasing use of psychotropic medications in children and adolescents, data regarding their efficacy and safety are limited. Endocrine and metabolic adverse effects are among the most concerning adverse effects of commonly used psychotropic medications. METHOD: Selective review of endocrine and metabolic effects of psychotropic medications in pediatric populations, with a focus on monitoring and management strategies. RESULTS: Because youth are still developing at the time of psychotropic drug exposure, most reference values need to be adjusted for gender and age. As in adults, youngsters receiving lithium require monitoring for thyroid dysfunction. Psychostimulants appear to cause mild reversible growth retardation in some patients, most likely because of decreased weight or slowing of expected weight gain; some patients may experience clinically significant reductions in adult height. Although still controversial, valproate use has been associated with an increased risk for polycystic ovary syndrome, in addition to causing weight gain. Although more data are required, children and adolescents appear to be at higher risk than adults for antipsychotic-induced hyperprolactinemia, weight gain, and possibly, associated metabolic abnormalities, which is of particular concern. CONCLUSIONS: Clinicians and caregivers need to be aware of potential endocrine and metabolic adverse effects of psychiatric medications. A careful selection of patients, choice of agents with potentially lesser risk for these adverse events, healthy lifestyle counseling, as well as close health monitoring are warranted to maximize effectiveness and safety.     

丙戊酸镁缓释片致全血细胞减少1例

丙戊酸镁对各型癫痫的治疗效果较好，同时也是美国食品药品监督管理局（FDA）批准用于治疗双相情感障碍的药物。丙戊酸盐的临床反应个体差异较大，消化道功能紊乱和肝功能异常是丙戊酸镁缓释片常见不良反应，而丙戊酸镁引起全血细胞减少鲜有报道。本案例报道了一例丙戊酸镁缓释片致全血细胞减少，以供临床参考。     

The effectiveness of mood stabilizers and antiepileptic medication for the management of behaviour problems in adults with intellectual disability: a systematic review

Background Psychotropic medications are used to manage behaviour problems in adults with intellectual disability (ID). One group of psychotropic medication are mood stabilizers such as lithium and some antiepileptic drugs. Method A comprehensive systematic review was performed to determine the evidence base for the effectiveness of mood stabilizers in the management of behaviour problems among adults with ID. Electronic searches of PsycInfo, Medline, Embase and Cinahl databases were conducted, as well as a thorough hand search for relevant literature. We reviewed primary trials relating to adults only that satisfied strict inclusion criteria. Results One randomized controlled trial (RCT) relating to lithium use and two non‐RCTs, one on lithium and the other on carbamazepine, were revealed. In addition, one prospective non‐controlled trial on sodium valproate and three retrospective case series studies were discovered, of which one considered the efficacy of lithium, one valproate and one topiramate. Conclusions The current evidence lends some support for the use of lithium and some antiepileptic mood stabilizer medication for the management of behaviour problems in adults with ID. However, because most studies reviewed here are riddled with obvious methodological constrains, the findings have to be interpreted with caution.     

A severe valproate overdose with complete recovery in a newborn

Valproate overdose, extensively described in adults and older children, has been reported in only 1 newborn: a 26-day-old female who developed a severe cerebral edema leading to a fatal outcome. Therefore, the consequences of valproate overdose are largely unknown in the neonatal period. Here, we present the clinical evolution of a 6-day-old newborn who developed hyperammonemic encephalopathy after the accidental administration of 310 mg/kg of oral valproate in a single dose. Despite the very high valproate and blood ammonia levels, he did not develop life-threatening complications and he completely recovered without sequels. His brain magnetic resonance imaging showed symmetric focal T1 prolonged signals in both globi pallidi that completely resolved over time, a neuroimaging pattern that was not previously described in valproate overdose. Our case report suggests that valproate overdose in newborns can be completely reversible even when the valproate and ammonium blood levels are very high.     

Effect of clozapine on polypharmacy

Prescribing patterns for a group of outpatients with schizophrenia were surveyed for changes after the initiation of clozapine. Data were drawn from computerized pharmacy records, direct case record reviews, and interviews with the attending psychiatrists. The number of patients with two or more psychotropic drugs decreased by 31 percent after the initiation of clozapine, and a trend toward the use of clozapine without additional neuroleptics was detected. Decreases occurred in the use of anticholinergic agents, carbamazepine, and benzodiazepines, but selective serotonin reuptake inhibitors and sodium valproate were more likely to be prescribed concomitantly with clozapine.     

Psychotropic discontinuation symptoms: a case of withdrawal neuroleptic malignant syndrome

INTRODUCTION: Although recent publications have focused on discontinuation symptoms of antidepressant medications, most classes of psychotropic drugs have been reported to have withdrawal symptoms. In light of the increased rate of psychotropic prescribing by primary care physicians, it is important for all physicians to be aware of psychotropic withdrawal symptoms. CASE REPORT: We report on a patient who developed symptoms consistent with neuroleptic malignant syndrome after abrupt discontinuation of a variety of psychotropic medications. METHODS: A MEDLINE search including both articles and letters to the editor was performed to identify symptoms reported in association with the discontinuation of psychotropic medications.     

Valproate-induced panhypogammaglobulinemia

Valproate is one of the most used anti-epileptic drugs. Its common side effects are nausea, vomiting, weight gain, hair loss, tremor, changes in behavior, slowed thinking and impaired liver function. Blood dyscrasias are also relatively frequent and a few studies reported changes in serum immunoglobulin concentrations with valproate treatment. We describe a case of panhypogammaglobulinemia with transient pancytopenia due to valproate. Pancytopenia was recovered after discontinuation of valproate but panhypogammaglobulinemia has been persisting. Intravenous immunoglobulin is being administrated monthly. Previous reports describe that other sodium channel blockers, such as phenytoin and carbamazepine, have been associated with hypogammaglobulinemia. This report also suggests that immunodeficiencies can be caused by valproate.     

Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine

In patients with bipolar disorder, recent brain imaging studies have reported cingulate cortex volume change. We performed a volumetric magnetic resonance imaging (MRI) study to assess the subregions of the cingulate gyrus; left anterior cingulate (LAC), left posterior cingulate (LPC), right anterior cingulate (RAC), and right posterior cingulate (RPC). Our sample consisted of bipolar patients that are either unmedicated (n=10), on valproate monotherapy (n=10) or on valproate plus quetiapine (n=10) versus healthy comparisons (n=10). Thirty right-handed bipolar disordered patients were recruited. Of them, 10 were first-applying patients who never had taken any drug for this condition (medication-naive group), 10 were on valproate treatment (valproate group) and 10 were on valproate plus quetiapine treatment (valproate plus quetiapine group). Cingulate gyrus volumes included both cortex and white matter. Drug-free patients had significantly smaller LAC and LPC volumes compared with valproate and valproate plus quetiapine groups and healthy controls. In addition, in post hoc comparisons, a trend toward significant difference was found between valproate plus quetiapine group and valproate group in regard to only LAC. Our findings suggest that valproate and quetiapine may have neuroprotective effects.     

Medication use in children and adolescents treated in the community for bipolar disorder

We assessed the use of mood stabilizers, stimulants, antipsychotic medication, and selective serotonin reuptake inhibitors in children being treated in the community for bipolar disorder (BPD). One hundred eleven patients were screened via parent phone interview for possible inclusion in a phenomenological study of BPD. Data were obtained on the patients' medication trials and side effects. The results of the study indicated that children and adolescents who carry a diagnosis of BPD are treated with a mean of 3.40 +/- 1.48 medications and have had a mean of 6.32 +/- 3.67 trials of psychotropic medication in the past. Ninety-eight percent have had a trial of a mood stabilizer or anticonvulsant, with the most common being valproate (79%), lithium (51%), and gabapentin (29%).     

Valproate hepatotoxicity: two new cases, a summary of others, and recommendations

There are two types of hepatotoxicity associated with valproate therapy--dose-related and idiosyncratic. The former may cause alterations in liver function as determined by laboratory examinations and is not associated with death. Idiosyncratic hepatotoxicity is rare, usually irreversible, and not predictable on the basis of laboratory monitoring. Two new cases are reported along with a selected, brief literature review and the authors' suggestions for the use of valproate.