Serge Beaulieu

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009

The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first-line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first-line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second-line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not-recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long-acting injection, and adjunctive ziprasidone continue to be first-line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third-line options.

Differential effects of adrenergic and corticosteroid hormonal systems on human short- and long-term declarative memory for emotionally arousing material.

The effects of adrenergic and corticosteroid hormonal systems on emotional memory were measured in 64 young men. Placebo, propranolol (40 or 80 mg; beta blocker), or metyiapone (corticosteroid synthesis inhibitor) was administered before the viewing of a story composed of emotional and neutral segments. Short- and long-term declarative memory for the story was assessed. Propranolol 40 mg had no effects on declarative memory. Propranolol 80 mg impaired short- and long-term declarative memory for emotionally arousing material. Metyrapone did not impair short-term declarative memory but impaired long-term declarative memory for emotionally arousing and neutral material. Results demonstrate that adrenergic and corticosteroid hormonal systems differentially affect declarative memory for emotionally arousing and neutral material, and suggest that interactions between adrenal hormonal systems modulate emotionally arousing declarative memory in humans.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments

OBJECTIVES Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. METHODS These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. RESULTS General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. CONCLUSIONS These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Pharmacological management of atypical antipsychotic-induced weight gain.

Excessive bodyweight gain was reported during the 1950s as an adverse effect of typical antipsychotic drug treatment, but the magnitude of bodyweight gain was found to be higher with the atypical antipsychotic drugs that were introduced after 1990. Clozapine and olanzapine produce the greatest bodyweight gain, ziprasidone and aripiprazole have a neutral influence, and quetiapine and risperidone cause an intermediate effect. In the CATIE study, the percentage of patients with bodyweight gain of >7% compared with baseline differed significantly between the antipsychotic drugs, i.e. 30%, 16%, 14%, 12% and 7% for olanzapine, quetiapine, risperidone, perphenazine (a typical antipsychotic) and ziprasidone, respectively (p < 0.001).Appetite stimulation is probably a key cause of bodyweight gain, but genetic polymorphisms modify the bodyweight response during treatment with atypical antipsychotics.In addition to nutritional advice, programmed physical activity, cognitive-behavioural training and atypical antipsychotic switching, pharmacological adjunctive treatments have been assessed to counteract excessive bodyweight gain. In some clinical trials, nizatidine, amantadine, reboxetine, topiramate, sibutramine and metformin proved effective in preventing or reversing atypical antipsychotic-induced bodyweight gain; however, the results are inconclusive since few randomized, placebo-controlled clinical trials have been conducted. Indeed, most studies were short-term trials without adequate statistical power and, in the case of metformin, nizatidine and sibutramine, the results are contradictory. The tolerability profile of these agents is adequate.More studies are needed before formal recommendations on the use of these drugs can be made. Meanwhile, clinicians are advised to use any of these adjunctive treatments according to their individual pharmacological and tolerability profiles, and the patient’s personal and family history of bodyweight gain and metabolic dysfunction.

Drug induced weight gain, an impediment to successful pharmacotherapy: focus on antipsychotics.

The antipsychotic drugs (APDs) are fundamental tools in current psychiatric practice. A new generation of agents, the atypical APDs, represents an important progress in the treatment of psychotic disorders. Unfortunately, some of them induce excessive body weight gain (BWG), obesity, hyperglycemia and dyslipidemia in the following order: clozapine approximately equal to olanzapine > quetiapine > risperidone > ziprasidone = aripiprazole. Appetite stimulation is probably the main mechanism of BWG and this is strongly correlated with the APD affinity for H1 (histaminergic) and alpha1 (adrenergic) receptors. A composed ratio of the APD affinity for diverse neurotransmitters involved in food intake (FI) regulation correlates with BWG as well. Endocrine/metabolic mechanisms, such as the activation of the hypothalamus-pituitary-adrenal axis, changes in insulin sensitivity (by conventional and atypical agents), hyperprolactinemia and gonadal dysfunction (by conventional APDs and risperidone) may also be involved. Importantly, patients with schizophrenia may have a genetically-based predisposition to appetite dysregulation, insulin resistance and endocrine imbalance involving gonadal steroids. Excessive BWG must be prevented or attenuated by proper drug selection, combining or switching agents, nutritional assistance and physical exercise. Amantadine. metformin and reboxetine proved to significantly lessen APD-induced BWG. Notwithstanding this, novel strategies are necessary to treat this side effect in a clinical population particularly prone to poor compliance and under a high risk of negative drug interaction.

Comparative effects of the antipsychotics sulpiride or risperidone in rats: I: Bodyweight, food intake, body composition, hormones and glucose tolerance

Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet.

Influence of the Central Nucleus of the Amygdala on the Content of Corticotropin-Releasing Factor in the Median Eminence

The central nucleus of the amygdala possesses numerous neurons containing corticotropin-releasing factor (CRF). This study demonstrates a striking decrease of the CRF-like immunoreactivity in the median eminence at both 1 and 2 weeks after bilateral lesions of the amygdaloid central nucleus. Lesion of the amygdaloid central nucleus did not alter the neurophysin-like immunoreactivity in the internal zone of the median eminence, indicating the integrity of the efferent neurophysin-containing fibers of the supraoptic and paraventricular hypothalamic nuclei. However, there was a concomitant decrease of neurophysin and CRF-like immunoreactivity in the external zone of the median eminence. These results substantiate the hypothesis that the amygdaloid central nucleus can influence the content of CRF-like material in the median eminence via a multisynaptic pathway involving the synthesis of CRF at the level of the paraventricular nucleus of the hypothalamus. The exact mechanism by which lesion of the amygdaloid central nucleus influences the CRF content in the median eminence remains to be determined.

Rapid cycling bipolar disorder – diagnostic concepts

OBJECTIVES This paper reviews the literature to examine the DSM-IV diagnostic criteria for rapid cycling in bipolar disorder. METHODS Studies on the clinical characteristics of rapid cycling bipolar disorder were reviewed. To identify relevant papers, literature searches using PubMed and MEDLINE were undertaken. RESULTS First observed in the prepharmacologic era, rapid cycling subsequently has been associated with a relatively poor response to pharmacologic treatment. Rapid cycling can be conceptualized as either a high frequency of episodes of any polarity or as a temporal sequence of episodes of opposite polarity. The DSM-IV defines rapid cycling as a course specifier, signifying at least four episodes of major depression, mania, mixed mania, or hypomania in the past year, occurring in any combination or order. It is estimated that rapid cycling is present in about 12-24% of patients at specialized mood disorder clinics. However, apart from episode frequency, studies over the past 30 years have been unable to determine clinical characteristics that define patients with rapid cycling as a specific subgroup. Furthermore, rapid cycling is a transient phenomenon in many patients. CONCLUSIONS While a dimensional approach to episode frequency as a continuum between the extremes of no cycling and continuous cycling may be more appropriate and provide a framework to include ultra-rapid and ultradian cycling, the evidence does not exist today to refine the DSM-IV definition in a less arbitrary manner. Continued use of the DSM-IV definition also enables comparisons between past and future studies, and it should be included in the next release of the ICD. Further scientific investigation into rapid cycling is needed. In addition to improving the diagnostic criteria, insight into neurophysiologic mechanisms of mood switching and episode frequency may have important implications for clinical care.

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.

Metformin plus sibutramine for olanzapine-associated weight gain and metabolic dysfunction in schizophrenia: A 12-week double-blind, placebo-controlled pilot study

Metformin (850-1700 mg) plus sibutramine (10-20 mg, n=13) or placebo (n=15) was administered for 12 weeks in olanzapine-treated chronic schizophrenia patients. Weight loss was similar in both groups: -2.8+/-3.2 kg vs. -1.4+/-2.6 kg. Except for preventing a triglyceride increase, the drug combination lacked efficacy for metabolic control in this clinical population.