Predicting Weight Gain in Patients Treated With Clozapine: The Role of Sex, Body Mass Index, and Smoking.

OBJECTIVES: Weight gain on clozapine is highly variable and poorly predictable. Its mechanisms are not well understood. This study explores the factors that predict weight gain between 3 and 12 months of clozapine therapy in community-dwelling patients. METHODS: We conducted a retrospective audit of patients attending an outpatient clozapine clinic. Weight change from 3 to 12 months of therapy was recorded, expressed as a percentage of the 3-month weight. Univariate analyses compared percent weight change according to sex, smoking status, country of birth, and baseline body mass index. Correlations between weight gain, age, and clozapine dose were explored. A general linear model identified independent predictors of weight gain. RESULTS: The mean weight change from 3 to 12 months in 117 patients was +3.1% (range, -17% to +30%). Females gained more weight than males (+5.5% vs +1.3%, P = 0.01), smokers gained more than nonsmokers (+5.1% vs +1.2%, P = 0.02), and obese patients gained less than normal or overweight individuals (0.15% vs 4.6% and 5.2%, respectively, P = 0.01). Age and clozapine dose had no relation to weight change. On multivariate analysis, baseline BMI and smoking status remained independent predictors of percent weight change in females. These 2 predictors explained 25% of weight change in females in the first 3 to 12 months of therapy. These associations were not observed in males. CONCLUSIONS: We hypothesize that smoking affects weight change by promoting clozapine metabolism to norclozapine via cytochrome P450 enzymes. Verifying this hypothesis and exploring the mechanisms underpinning the sex dichotomy are areas for further research.

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine.

OBJECTIVE: The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. METHOD: A systematic review of English-language MEDLINE articles was undertaken. CONCLUSIONS: Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine.

Clozapine (CZ) has superior efficacy to other antipsychotic agents in the treatment of schizophrenia and has been extensively used in clinical practice. ATP-binding cassette (ABC) transporter proteins are responsible for the distribution of various molecules as well as drugs across extracellular and intracellular membranes, including the blood-brain barrier. Genetic variations in these proteins can account for differences in treatment response. We investigated the influence of ABCB1 rs1045642 and ABCC1 rs212090 single-nucleotide polymorphisms (SNPs) on CZ serum level, clinical outcome, and changes in body mass index (BMI) in the first year of CZ treatment. These polymorphisms influenced baseline BMI in males (p=0.009 and 0.054, B1 and C1, respectively), changes in BMI in males after 3 (p=0.026, ABCB1) and 12 months (p=0.022, ABCC1) of CZ treatment, and level of diastolic pressure (p=0.002 and 0.051, respectively). The combination of ABCB1 + ABCC1 homozygote SNPs was associated with increased CZ and norclozapine serum levels (p=0.054 and 0.010, respectively). ABC transporter SNPs could be potential biomarkers for CZ-induced weight gain and cardiovascular complications. Further pharmacogenetic research is warranted to help clinicians with their treatment decision, including concomitant use of drugs and prevention of side effects.

CYP2C19*17 protects against metabolic complications of clozapine treatment.

OBJECTIVES: Clozapine (CZ) is the most effective drug for managing treatment-resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients. METHODS: We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes. RESULTS: Thirty-nine percent of genotyped patients were carriers of the CYP2C 19*17 polymorphism. This group demonstrated significantly higher NCZ serum levels, and significantly lower fasting glucose (5.66 ± 1.19 vs 6.72 ± 3.01 mmol/l, P = 0.009) and Hb1Ac (35.36 ± 4.78 vs 49.40 ± 20.60 mmol/mol, P = 0.006) levels compared to non-carriers of this polymorphism. CZ-treated patients with CYP2C19*17/*17 had a significantly lower prevalence of diabetes as well as a higher likelihood of clinical improvement of their schizophrenia, compared to those without this polymorphism (P = 0.012 and P = 0.031, respectively). CONCLUSIONS: Our data suggest that CYP2C19*17 ultra-rapid-metaboliser status is a protective factor against the development of diabetes during clozapine treatment, and increases the likelihood of improvement in schizophrenia. The role of NCZ in treatment response and side effects, including metabolic syndrome, warrants further pharmacogenetic, pharmacokinetic and pharmacodynamic studies.

Factors influencing psychotropic prescription by non-psychiatrist physicians in a nursing home for the elderly in Brazil.

CONTEXT AND OBJECTIVE: Although psychotropics are one of the classes of medications most prescribed in nursing homes for the elderly, studies examining prescribing patterns are limited in both number and scope. The present study was undertaken to investigate factors associated with general psychotropic use in a nursing home in Brazil. DESIGN AND SETTING: Retrospective observational study at the Nursing Home for the Elderly, Institute of Biosciences, Universidade Estadual Paulista. METHODS: Information on prescriptions was retrieved from the medical records of 108 elderly residents in a nursing home. Sixty-five of these patients, with mean age 74.5 years (+/-standard deviation 9.4 years), who were taking medications on a regular basis, comprised the sample. The effects of demographic and clinical variables on the psychotropic prescription pattern were examined. RESULTS: Females were more likely to receive psychotropics (p = 0.038). Individuals on medicines for cardiovascular diseases received psychotropics less frequently (p = 0.001). The number of prescribed psychotropics correlated negatively with both age (p = 0.009) and number of non-psychotropic drugs (p = 0.009). CONCLUSIONS: Although preliminary, the present results indicated that cardiovascular disease was the clinical variable that most influenced psychotropic prescription. Physicians' overconcern regarding drug interactions might at least partially explain this result. Further investigations involving larger sample sizes from different regions are warranted to confirm these findings.

Ultrarapid clozapine metabolism and CYP2D6 gene duplication in a patient with schizophrenia.

An optimal clozapine serum level is required for both optimization of clinical response and minimization of troublesome or some of the life-threatening side effects. Serum levels can be influenced by comedication that can cause phenoconversion. When norclozapine/clozapine serum levels and ratios are consistently and significantly lower/higher than expected and there are no concomitant drugs that could account for these findings, further investigation of the genetic variants of CYP1A2, 2D6 and 3A4 are warranted.

Urinary pH in panic disorder.

Urinary pH was evaluated in panic disorder (PD) patients compared with both psychiatric and healthy control subjects. Fourteen PD patients, eight major depressive disorder (MDD) patients, and 14 healthy control (HC) subjects were examined. All patients were drug-free and met DSM-IV diagnostic criteria. The PD patients had lower urinary pH and higher levels of anxiety than both MDD and HC subjects. Additionally, urinary pH inversely correlated with anxiety levels. Although preliminary, these findings suggest that PD patients have lower urinary pH than MDD and HC subjects. Future studies that simultaneously examine both urinary and blood pH in larger numbers of PD patients and patients with other anxiety disorders, before and after treatment, need to be conducted.

Higher than expected clozapine serum level and clozapine/norclozapine ratio due to CYP450 gene polymorphisms.

AIMS: We investigated a case of the unexpectedly high clozapine/norclozapine serum levels in a non-smoker, female patient. METHOD: The RFLP genotype method was used for the loss-of-function CYP450 gene polymorphisms detection. RESULTS: The genotype revealed the presence of CYP2D6*41/*41, rs28371725, NM_000106.5:c.985+39G>A and CYP1A2*1/*1D rs35694136, NM_000761.4:c.-1635delT. CONCLUSION: An appropriate clozapine serum level is required for both optimization of clinical response and avoidance of troublesome, or even life-threatening side effects. Although not the only factor, genetic polymorphisms responsible for the metabolism of clozapine play an important role towards such goals. Pharmacogenetic tests can guide dose adjustment in order to obtain an optimum serum level, which can lead to a better therapeutic response and minimization of harmful side effects.

Neuropsychological performance and regional cerebral blood flow in obsessive-compulsive disorder.

Convergent findings from neuropsychological and neuroimaging studies have suggested that neural dysfunction in frontal-subcortical circuits may play a central role in the pathophysiology of obsessive-compulsive disorder (OCD). To further examine the relationship between these two sets of findings we investigated both neuropsychological functions and regional cerebral blood flow (rCBF) in a combined study. Fourteen unmedicated patients fulfilling DSM-IV criteria for OCD and 14 healthy controls matched for age, gender, handedness, and education were assessed on neuropsychological tests that included Trail Making Test (TMT), Rey Complex Figure Test (RCF) (copy and 5-min recall), Verbal Fluency Test (VFT), and Wisconsin Card Sorting Test (WCST). rCBF was studied with 99 mTc-hexamethyl-propyleneamine-oxime (HMPAO) single photon emission computed tomography (SPECT). Patients performed more poorly than controls (P<.05) on RCF (copy), VFT, and WCST (perseverative errors). Spearman's correlations indicated that severity of OCD correlated inversely with performance on the RCF (copy and recall scores) and positively with rCBF in the right thalamus. Positive correlations were observed between nonperseverative errors (WCST) and rCBF in frontal areas and anterior cingulate. Perseverative errors (WCST) correlated negatively with rCBF in the right thalamus. These findings are consistent with most previously published studies and suggest neural dysfunctions in the frontal-subcortical circuits probably more pronounced in the right hemisphere. They also extend the existing research, showing associations between deficits in cortical-subcortical circuitry and performance on neuropsychological tests of controlled attention and visuospatial functions.

Elevated thalamic and prefrontal regional cerebral blood flow in obsessive-compulsive disorder: a SPECT study.

Functional neuroimaging studies have pointed to a possible role of cerebral circuits involving the prefrontal and anterior cingulate cortices, the striatum, and thalamus in the pathophysiology of obsessive-compulsive disorder (OCD). Regional cerebral blood flow (rCBF) of 16 drug-free Brazilian patients with OCD and 17 healthy subjects matched for age, gender, handedness and level of education was measured with [99m-Tc] HMPAO single photon emission computed tomography. Analysis of covariance identified four regions of interest with significantly higher rCBF: the right superior and inferior frontal cortex and the right and left thalamus. Positive correlations between symptom severity measured by Clinical Global Impression scores and rCBF were found in the right and left inferior frontal lobes and in the right basal ganglia. Compulsive behavior was inversely correlated with rCBF in the right thalamus, and duration of illness correlated positively with rCBF in the right and left superior frontal lobes and with the right thalamus. The findings of this SPECT study conducted in Brazil are in agreement with prior studies and provide additional support for the involvement of prefrontal-subcortical circuits in the pathophysiology of OCD. Furthermore, the study suggests that similar brain mechanisms appear to be involved cross-culturally.

Acute psychotic disorders induced by topiramate: report of two cases.

We report on two epileptic patients who developed acute psychosis after the use of topiramate (TPM). One patient exhibited severe psychomotor agitation, heteroaggressiveness, auditory and visual hallucinations as well as severe paranoid and mystic delusions. The other patient had psychomotor agitation, depersonalization, derealization, severe anxiety and deluded that he was losing his memory. Both patients had to be taken to the casualty room. After interruption of TPM in one patient and reduction of dose in the other, a full remission of the psychotic symptoms was obtained without the need of antipsychotic drugs. Clinicians should be aware of the possibility of development of acute psychotic symptoms in patients undergoing TPM treatment.

Associations, causation and model in psychiatry / Associações, causas e modelos em psiquiatria

This paper discusses models, associations and causation in psychiatry. The different types of association (linear, positive, negative, exponential, partial, U shaped relationship, hidden and spurious) between variables involved in mental disorders are presented as well as the use of multiple regression analysis to disentangle interrelatedness amongst multiple variables. A useful model should have internal consistency, external validity and predictive power; be dynamic in order to accommodate new sound knowledge; and should fit facts rather than they other way around. It is argued that whilst models are theoretical constructs they also convey a style of reasoning and can change clinical practice. Cause and effect are complex phenomena in that the same cause can yield different effects. Conversely, the same effect can have a different range of causes. In mental disorders and human behaviour there is always a chain of events initiated by the indirect and remote cause; followed by intermediate causes; and finally the direct and more immediate cause. Causes of mental disorders are grouped as those: (i) which are necessary and sufficient; (ii) which are necessary but not sufficient; and (iii) which are neither necessary nor sufficient, but when present increase the risk for mental disorders.

Este artigo discute modelos, associações e fatores causais em psiquiatria. Os diferentes tipos de associação (linear, positiva, negativa, exponencial, parcial, em forma de U, escondida e fortuita) entre as variáveis envolvidas na ocorrência de transtornos mentais são apresentados, bem como o uso da análise de regressão múltipla para analisar covariâncias entre múltiplas variáveis. Um modelo, para ser útil, deve ter consistência interna, validade externa e poder preditivo, ser dinâmico para incorporar novas descobertas e adequar-se aos fatos, e não o contrário. Os modelos, embora sejam construtos teóricos, implicam em uma dada forma de pensar e têm implicações para a prática clínica. Causa e efeito constituem um fenômeno complexo, podendo a mesma causa ter diferentes efeitos e, inversamente, o mesmo efeito, uma gama diferente de causas. Nos transtornos mentais e no comportamento humano há sempre uma cadeia de eventos iniciada por uma causa indireta e remota; seguida por causas intermediárias; e por último, uma causa direta e imediata. As causas dos transtornos mentais podem ser agrupadas em: (i) necessárias e suficientes; (ii) necessárias, mas não suficientes; e (iii) nem necessárias nem suficientes, mas se presentes, aumentam o risco para a ocorrência de transtornos mentais.

Mortalidade em pacientes psiquiátricos: revisão bibliográfica / Mortality in psychiatric patients: literature review

OBJETIVO: Avaliar as informações referentes às taxas de mortalidade em pacientes psiquiátricos publicadas na literatura científica. MÉTODOS: Nesta revisão bibliográfica (bases de dados, sites e periódicos especializados) foram selecionados estudos descritivos e interpretativos que avaliaram as seguintes dimensões: caracterização sociodemográfica, co-morbidades clínicas, tempo de tratamento e diagnósticos relacionados à mortalidade psiquiátrica. As bases de dados avaliadas foram Medline, SciELO e LILACS. RESULTADOS: Os estudos selecionados sobre o tema sugerem que indivíduos com transtornos mentais maiores têm menor tempo de sobrevida em relação à população geral, e há diferenças significativas de mortalidade entre pacientes institucionalizados e aqueles que freqüentam serviços extra-hospitalares. A política de desinstitucionalização do paciente psiquiátrico, que se iniciou no último século, tem causado redução dos leitos psiquiátricos em todos os países; seus efeitos para a saúde geral dos doentes mentais ainda não estão muito claros e necessitam de mais investigações. CONCLUSÃO: É necessária a implantação de intervenções preventivas e terapêuticas que visem à saúde geral dos pacientes psiquiátricos em todos os níveis de assistência de saúde mental.

OBJECTIVE: The objective of this paper is to review the literature regarding mortality rates of psychiatric patients. METHODS: The authors carried out a systematic review (databases, sites and specialized journals) on studies about mortality of psychiatric patients. Medline, SciELO and LILACS databases were searched. The review included those studies that assessed the following: socioeconomic factors, clinic diagnosis, length of stay, diagnostic categories and mortality. RESULTS: The findings point to the fact that individuals with major mental disorders clearly present life expectation diminished as compared to general population and this mortality rate is even greater in those patients outside hospital. The trend towards deinstitutionalization of psychiatric patients that took place in the last century has reduced psychiatric beds all over the world. As a consequence there has been an important drawback in general health of those with mental disorders. CONCLUSION: There is a need of implementation of preventive and therapeutic programs aiming at the improvement of general health of psychiatric patients at all levels of mental health facilities.

Prevalência de transtornos mentais em trabalhadores de uma universidade pública do estado de São Paulo / Prevalence of mental disorders in university workers from a state university in São Paulo

Em uma amostra com 552 trabalhadores de uma universidade pública do interior do estado de São Paulo, realizou-se um estudo epidemiológico de corte transversal, objetivando estimar a prevalência anual de Suspeição para Transtornos Mentais (STM). Foi utilizado o Questionário de Morbidade Psiquiátrica de Adultos-QMPA (SANTANA, 1982) em versão validada para uso em população trabalhadora (GUIMARÃES, 1992). Encontrou-se uma prevalência anual de 35% de STM. Associações estatisticamente significativas foram obtidas entre STM e: gênero (p = 0,01); estado civil (p = 0,05); religião (p = 0,05); renda familiar (p = 0,01); maior número de faltas/mês (p = 0,00). Não foram encontradas associações estatisticamente significativas entre STM e: idade, escolaridade, local de trabalho. Obteve-se somente uma tendência à associação entre STM e mudança de local de trabalho no último ano (p = 0,08). A alta prevalência de STM encontrada alerta para a magnitude do problema na organização, evidenciando a urgência da implantação de medidas preventivas relativas aos fatores psicossociais de risco e a necessidade de intervenções adequadas para o enfrentamento dos mesmos.

In a cross-sectional study designed to assess the annual prevalence of Suspected Cases of Mental Disorders (SCMD), the Adult Psychiatric Morbidity Questionnaire (QMPA; (Santana, 1982) adapted to the Brazilian working population (Guimarães, 1992) was administered to a stratified sample of 552 university workers from a State University in the city of Campinas, São Paulo. The annual prevalence of SCMD was 35%. Moreover, SCMD were significantly associated with gender (p=0.01), marital status (p=0.05), religion (p=0.05), income (p-0.01), absenteeism from work (p=0.00) on one hand; and not associated with age, education, on the other. The results showed only a tendency of association between SCMD and the changing of workplace during the previous year.(p=0.08). The high prevalence of SCMD highlights the magnitude of the problem and emphasizes the urgent need of correct preventive measures, actions and interventions to cope with the psychosocial risk factors.

Factors influencing psychotropic prescription by non-psychiatrist physicians in a nursing home for the elderly in Brazil

CONTEXT AND OBJECTIVE: Although psychotropics are one of the classes of medications most prescribed in nursing homes for the elderly, studies examining prescribing patterns are limited in both number and scope. The present study was undertaken to investigate factors associated with general psychotropic use in a nursing home in Brazil. DESIGN AND SETTING: Retrospective observational study at the Nursing Home for the Elderly, Institute of Biosciences, Universidade Estadual Paulista. METHODS: Information on prescriptions was retrieved from the medical records of 108 elderly residents in a nursing home. Sixty-five of these patients, with mean age 74.5 years (± standard deviation 9.4 years), who were taking medications on a regular basis, comprised the sample. The effects of demographic and clinical variables on the psychotropic prescription pattern were examined. RESULTS: Females were more likely to receive psychotropics (p = 0.038). Individuals on medicines for cardiovascular diseases received psychotropics less frequently (p = 0.001). The number of prescribed psychotropics correlated negatively with both age (p = 0.009) and number of non-psychotropic drugs (p = 0.009). CONCLUSIONS: Although preliminary, the present results indicated that cardiovascular disease was the clinical variable that most influenced psychotropic prescription. Physicians' overconcern regarding drug interactions might at least partially explain this result. Further investigations involving larger sample sizes from different regions are warranted to confirm these findings.

CONTEXTO E OBJETIVO: Embora os psicotrópicos sejam uma das classes de medicações mais prescritas em abrigos para idosos, os estudos avaliando o seu padrão de prescrição são limitados em número e escopo. Este estudo visou investigar os fatores associados ao uso de psicofármacos em um abrigo para idosos no Brasil. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo observacional realizado no Abrigo da Velhice de Rio Claro, Instituto de Biociências, Universidade Estadual Paulista. MÉTODOS: Dados sobre prescrições foram extraídos dos prontuários médicos dos 108 idosos moradores do abrigo. Sessenta e cinco sujeitos (idade média ± desvio padrão = 74,5 ± 9,4 anos), em uso regular de medicação, constituíram a amostra. Foram examinados os efeitos das variáveis sociodemográficas e clínicas sobre o padrão de prescrição de psicofármacos. RESULTADOS: As mulheres recebiam mais psicofármacos (p = 0.038); indivíduos em uso de medicações para doenças cardiovasculares recebiam menos psicofármacos (p = 0.001). Houve correlação negativa entre número de psicofármacos prescritos e, ambos, idade (p = 0.009) e número de medicações clínicas (p = 0.009). CONCLUSÃO: Embora preliminares, os resultados indicam as doenças cardiovasculares como a variável clínica que mais influenciou a prescrição de psicofármacos. Uma excessiva precaução por parte dos clínicos pode explicar parcialmente este resultado. Novas investigações, com amostras maiores e de diferentes regiões são desejáveis para confirmação destes dados.