Antimanic Effects Research Articles

Neuroanatomical Profile of Antimaniac Effects of Histone Deacetylases Inhibitors

An increasing number of studies have evaluated the potential therapeutic relevance of histone deacetylases (HDAC) inhibitors in mood disorder including bipolar disorder (BD). It has been suggested that the anterior limbic, which controls impulsivity and psychosis, is dysfunctional in BD. The present studies aims to evaluate the effects of microinjection of HDAC inhibitors in the ventricle, amygdala, striatum, prefrontal, and hippocampus on m-amphetamine-induced manic-like behavior in rats. Rats were given a single intracerebral (in the ventricle, amygdala, striatum, prefrontal, or hippocampus) injection of artificial cerebrospinal fluid, sodium butyrate (SB), or valproate (VPA) followed by an intraperitoneal injection of saline or m-AMPH 2 h before the open-field task. The activity of HDAC was evaluated in amygdala, striatum, prefrontal, and hippocampus of animals. The microinjection of SB and VPA in the ventricle, amygdala, striatum, and prefrontal, but not in hippocampus blocked the hyperactivity induced by m-AMPH. In addition, SB and VPA inhibited the HDAC activity; however, this effect varied depending on the experimental procedure and the brain structure evaluated. Our results suggest that the antimanic effects of SB and VPA, HDAC inhibitors, are related to the amygdala, striatum, and prefrontal, but not the hippocampus. More studies are needed to clarify the therapeutic effects of the HDAC inhibitor in BD and thereby develop new drugs.

Tourette's Syndrome and Type 2 Bipolar Disorder

Back to table of contents Previous article Next article LettersFull AccessTourette's Syndrome and Type 2 Bipolar DisorderLuís Fonseca, Joana Damásio, Marina Magalhães, and Joaquim DuarteLuís FonsecaPsychiatry and Mental Health Department, Braga Hospital, Braga, PortugalSearch for more papers by this author, Joana DamásioNeurology Department, Porto Hospital Centre, Porto, PortugalSearch for more papers by this author, Marina MagalhãesNeurology Department, Porto Hospital Centre, Porto, PortugalSearch for more papers by this author, and Joaquim DuartePsychiatry and Mental Health Department, Braga Hospital, Braga, PortugalSearch for more papers by this authorPublished Online:1 Jan 2011AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Tourette's syndrome is an inherited, childhood-onset neuropsychiatric disorder characterized by a fluctuating course of multiple chronic motor and phonic tics. Around 88% of Tourette's syndrome patients have comorbidity, the most common being attention-deficit/hyperactivity disorder, followed by obsessive compulsive disorder.1Case ReportA 34-year-old male patient with a history of Tourette's syndrome was seen for acute onset of insomnia, irritability, and overspending. He also presented slight neck jerking. He had been medicated with 600 mg of sulpiride and 10 mg of haloperidol for Tourette's syndrome. At this time, 500 mg of valproate was prescribed with symptomatic improvement. Antipsychotic medication was maintained. Four months later he presented with depressive mood, anhedonia, insomnia, loss of appetite, and diminished ability to concentrate of 1 month duration. Fluvoxamine was prescribed and titrated to 100 mg while the other drugs were maintained. Again he improved.Nine months later, the patient was seen for acute onset of insomnia, overspending, dysphoric mood, sexual disinhibition, and megalomaniac thoughts, and he was admitted to our unit. A brain MRI and thorough lab work returned normal results. Valproate was titrated to 1,000 mg, and we added 300 mg of quetiapine. Haloperidol and sulpiride were stopped without the worsening of neck jerking or the onset of new tics. Three weeks later, he presented no psychiatric symptoms and was discharged home.At the age of 13, our patient had acutely developed cervical motor tics. He started haloperidol, titrated to 6 mg, with symptomatic improvement. When he turned 18 the motor tics worsened, new ones involving the superior limbs appeared, and the onset of vocal tics (shouting repeatedly during his speech and coprolalia) occurred. Haloperidol augmentation to 10 mg improved these.Until the age of 23, the tics presented a waxing and waning course. At this age, cervical and mouth tics slightly improved and others began (scratching the genitalia, clothes pruning). Haloperidol was then stopped, and sulpiride titrated to 600 mg improved these symptoms. A slight neck jerking remained up to the time he presented to our unit.The clinical picture that emerged 9 months after the depressive syndrome was clearly a hypomanic state. The diagnosis of bipolar disorder type II could then be confidently made.2Hypomania could be considered an iatrogenic effect of antidepressant medication. However, it is unlikely due to the antimanic effect of valproate and sulpiride3 and the 9 months that had lapsed since the antidepressant was prescribed.DiscussionComorbidity between Tourette's syndrome and bipolar disorder, although infrequent, has been reported.4 A modulation defect of the mesencefalic nuclea in certain areas of the cortical-limbic system, ventral striatum, and sensory motor cortical regions could explain the association. The onset of mania or bipolar disorder in neuropsychiatric disorders with predominant subcortical dysfunction (e.g., Huntington's) further supports it.1,5The onset of vocal tics at the age of 18 fulfilled diagnostic criteria for Tourette's syndrome.5 Currently, neck jerking is the only remaining tic. This is consistent with the known decrease of tic frequency and intensity during adolescence in about two-thirds of children with Tourette's syndrome, as well as its frequent remission in adulthood.6Psychiatry and Mental Health Department, Braga Hospital, Braga, PortugalNeurology Department, Porto Hospital Centre, Porto, PortugalPsychiatry and Mental Health Department, Braga Hospital, Braga, Portugal1. Robertson M: Mood disorders and Gilles de la Tourette's syndrome: an update on prevalence, etiology, comorbidity, clinical associations and implications. J Psychosom Res 2006; 61:349–358Crossref, Medline, Google Scholar2. Muller-Oerlinghausen B , Berghofer A , Bauer M: Bipolar disorder. Lancet 2002; 19:359241–247Crossref, Google Scholar3. Cristhie J , Whalley L , Hunter R, et al.: Sulpiride treatment of acute mania with a comparison of the effects of plasma hormone concentrations of lithium and sulpiride treatment. J Affective Disord 1989; 16:115–120Crossref, Medline, Google Scholar4. Berthier M , Kulisevsky J , Campos V: Bipolar disorder in adult patients with Tourette's syndrome: a clinical study. Biol Psychiatry 1998; 43:364–370Crossref, Medline, Google Scholar5. Harris K , Singer H: Tic disorders: neural circuits, neurochemistry and neuroimmunology. J Child Neurol 2006; 21:678–689Crossref, Medline, Google Scholar6. Bloch M , Leckman J , Zhu H, et al.: Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology 2005; 65:1253–1258Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 23Issue 1 Winter 2011Pages E26-E26 Metrics PDF download History Published online 1 January 2011 Published in print 1 January 2011

Pharmacology and efficacy of asenapine for manic and mixed states in adults with bipolar disorder

Asenapine sublingual is a novel atypical antipsychotic approved in August 2009 for the acute treatment of schizophrenia, as well as for manic or mixed episodes as part of adult bipolar I disorder. Asenapine’s in vitro profile is similar to other atypical antipsychotic agents insofar as there is higher affinity for serotonin 5-HT2A versus dopamine D2 receptors. Asenapine exhibits a unique effect on monoamine, histamine and muscarinic receptor affinities, as well as effects on NMDA and AMPA receptors. This pharmacodynamic signature may mediate its symptom relief in positive, negative and mood symptoms, as well as conferring upon this agent an improved tolerability and safety profile when compared with some atypical agents. Asenapine has a relatively low propensity for changes in metabolic parameters, body composition, sedation/somnolence and extrapyramidal side effects, and is not associated with prolactin elevation or clinically significant electrocardiographic changes. Asenapine is available only in sublingual formulation, which has advantages (e.g., patient acceptance, compliance, difficulty swallowing) as well as disadvantages (i.e., patients are encouraged not to eat or drink within 10 min of administration). Its efficacy in mania is unequivocally established as is the sustaining of its acute antimanic effect. Its antidepressant and recurrence prevention effects in bipolar disorder are under investigation, as is its possible role in major depressive disorder.

Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD.

This report considers the conceptual and methodological concerns confronting clinical investigators seeking to generate knowledge regarding the tolerability and benefits of pharmacotherapy in geriatric bipolar disorder (BD) patients. There is continuing need for evidence-based guidelines derived from randomized controlled trials that will enhance drug treatment of geriatric BD patients. Therefore, we present the complex conceptual and methodological choices encountered in designing a multisite clinical trial and the decisions reached by the investigators with the intention that study findings be pertinent to, and can facilitate, routine treatment decisions. Guided by a literature review and input from peers, the tolerability and antimanic effects of lithium and valproate were judged to be the key mood stabilizers to investigate with regard to treating bipolar I disorder manic, mixed, and hypomanic states. The patient selection criteria are intended to generate a sample that not only experiences common treatment needs but also represents the variety of older patients seen in university-based clinical settings. The clinical protocol guides titration of lithium and valproate to target serum concentrations, with lower levels allowed when necessitated by limited tolerability. The protocol emphasizes initial monotherapy. However, augmentation with risperidone is permitted after three weeks when indicated by operational criteria. A randomized, controlled trial that both investigates commonly prescribed mood stabilizers and maximizes patient participation can meaningfully address high-priority clinical concerns directly relevant to the routine pharmacologic treatment of geriatric BD patients.

Rapid Onset of Neurological Symptoms and Lithium Toxicity on Starting Meloxicam

This year marks the 60th anniversary of the first observation of lithium's anti-manic effects by John Cade [1]. Lithium remains the first-line therapeutic choice for preventing bipolar mania. Being a salt, lithium is excreted by the kidney; and concomitant agents that alter renal function, such as non-steroidal anti-inflammatory drugs (NSAIDs), can precipitate toxicity. NSAIDs inhibit the cyclooxygenase enzyme, thereby reducing the production of renal prostaglandins, which regulate the glomerular hydrostatic pressure. NSAIDs thus decrease renal blood flow and the glomerular filtration rate, which in turn stimulates sodium and lithium [2] reabsorption within the proximal tubules and leads to an increase in serum lithium concentration. We report the case of a 49-year-old woman with well-controlled bipolar disorder who presented with lethargy, diarrhoea, nausea, vomiting, hypersalivation, tremors, muscle weakness and confusion. These side-effects reportedly developed 3 days after being started on meloxicam 15 mg day^−1. There was no past history of renal disease and laboratory records back to 2002 were all normal. The patient had no allergies and was not known to use illicit substances.

Mania and attention-deficit/hyperactivity disorder: common symptomatology, common pathophysiology and common treatment?

Attention-deficit/hyperactivity disorder (ADHD) and mania show broad symptom overlap, and high comorbidity exists between ADHD and bipolar disorder. This raises the question concerning common neurobiological pathomechanisms and concerning common treatments. On genetic, biochemical, electrophysiological, brain morphological and neuropsychological levels, the commonalities of ADHD and mania and the commonalities between ADHD and bipolar disorder (independent of manic state) are outlined. An intriguing finding is that both ADHD and mania are characterized by an unstable wakefulness regulation assessed by EEG measures of vigilance, by ratings of sleepiness and by deficits in sustained attention tasks. In both mania and ADHD, this unstable wakefulness regulation is supposed to be a central pathogenetic factor leading to attention deficits and inducing the hyperactive, impulsive and sensation-seeking behavior as an autoregulatory attempt to stabilize wakefulness by increasing external stimulation. Evidence is accumulating to suggest that psychostimulants do not have a high risk of triggering or aggravating mania, but might even be a treatment option in acute mania. ADHD and mania share many symptoms and several pathogenetic aspects. The common belief that stimulants are contraindicated in mania has been challenged, and controlled trials to study the possible antimanic effects of vigilance-stabilizing drugs such as stimulants are justified and necessary.

Is Anticonvulsant Treatment of Mania a Class Effect? Data from Randomized Clinical Trials

Our aim was to evaluate the efficacy and tolerability of anticonvulsant agents for the treatment of acute bipolar mania and ascertain if their effects on mania are a "class" effect. We conducted a systematic review of randomized controlled trials (RCTs) with placebo or active comparator, in acute bipolar mania in order to summarize available data on anticonvulsant treatment of mania/mixed episodes. We searched (PubMed/MEDLINE) with the combination of the words "acute mania" and "clinical trials" with each one of the following words: "anticonvulsants/antiepileptics,""valproic/valproate/divalproex,""carbamazepine,""oxcarbazepine,""lamotrigine,""gabapentin,""topiramate,""phenytoin,""zonisamide,""retigabine,""pregabalin,""tiagabine,""levetiracetam,""licarbazepine,""felbamate," and "vigabatrin." Original articles were found until November 1, 2008. Data from 35 randomized clinical trials suggested that not all anticonvulsants are efficacious for the treatment of acute mania. Valproate showed greater efficacy in reducing manic symptoms, with response rates around 50% compared to a placebo effect of 20-30%. It appears to have a more robust antimanic effect than lithium in rapid cycling and mixed episodes. As valproate, the antimanic effects of carbamazepine have been demonstrated. Evidences did not support the efficacy of the gabapentin, topiramate as well as lamotrigine as monotherapy in acute mania and mixed episodes. Oxcarbazepine data are inconclusive and data regarding other anticonvulsants are not available. Anticonvulsants are not a class when treating mania. While valproate and carbamazepine are significantly more effective than placebo, gabapentin, topiramate, and lamotrigine are not. However, some anticonvulsants may be efficacious in treating some psychiatric comorbidities that are commonly associated to bipolar illness.

Are Psychostimulants a Treatment Option in Mania?

Mania and attention-deficit hyperactivity disorder (ADHD) show a high degree of symptom overlap and comorbidity. Clinical trials and case reports indicate that psychostimulants do not or only rarely trigger or aggravate manic episodes but can even produce rapid and pronounced antimanic effects. An explanatory model is presented here in which the sensation seeking, hyperactive behaviour observed in mania and ADHD is interpreted as an autoregulatory attempt to stabilize vigilance by increasing external stimulation. Accordingly, patients with both mania and ADHD show rapid declines to lower vigilance levels (e.g., sleep spindles in EEG) under resting conditions with low external stimulation. The "paradoxical" antimanic effect of psychostimulants possibly results from their vigilance stabilizing properties.

Circadian polymorphisms associated with affective disorders.

BackgroundClinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies.MethodsFour groups of subjects were recruited from several sources: 1) bipolar proband-parent trios or sib-pair-parent nuclear families, 2) unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3) sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4) a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples.ResultsIn NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample.ConclusionAlong with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may influence mood disorders, perhaps ultimately through regulation of MAOA and its modulation of dopamine transmission. Twenty-three associations of circadian polymorphisms with affective symptoms met nominal significance criteria (P < 0.05), whereas 15 would be expected by chance, indicating that many represented false discoveries (Type II errors). Some evidence of replication has been gathered, but more studies are needed to ascertain if circadian gene polymorphisms contribute to susceptibility to affective disorders.

Old but still gold: Lithium in stabilizing the mood

Byline: Richard. Balon Many, if not all, great discoveries in psychopharmacology resulted, as Donald Klein noted,[sup] [1] chance observations of unexpected clinical benefits or as inadvertent outcomes of blind pharmaceutical searches. One of such discoveries, by Cade J[sup] [2] in the late 1940's, was the calming anti-manic effect of lithium. Cade first noticed a calming effect of lithium in guinea pigs. He decided to test lithium in various mental illnesses, including mania and melancholia (interestingly, he ingested lithium himself first to ensure its safety in humans). The calming effect of lithium in mania was very robust, and Cade even speculated that mania may be caused by some lithium deficiency. His seminal discovery ultimately led to a revolutionary new approach - we not only had and have an agent to treat mania and manic-depressive illness (what we call today a bit strangely bipolar illness), but we got an agent that is useful to prevent future episodes of this illness and to stabilize fluctuations of mood. However, one should note that William Hammond first reported on the usefulness of lithium in manic states as early as in 1871, which has not been mentioned in the textbooks.[sup] [3] While Cade[sup] [2] is rightfully given credit for the discovery of the anti-manic properties of lithium, it is not clear whether this discovery would not have remained just an interesting observation without wide-scale clinical application but for the work of other giants of the golden era of psychopharmacology. The main student and proponent of lithium use was the Danish psychiatrist Mogens Schou (1918-2005). Schou started to examine the clinical properties of lithium as a young psychiatrist during the early 1950's. Lithium remained his life-long obsession. In his early exploration of lithium, he designed one of the first partly open and partly randomized and placebo-controlled trials of this agent. His early research confirmed the previous finding that lithium has anti-manic properties.[sup] [4] Schou spent endless time researching all aspects of lithium's effect on the body and the brain, and published on a wide range of issues, from lithium in the heart muscle, to lithium's teratogenicity, and the effect of prolonged lithium administration on cerebral monoamine neurons in rats. His work cemented the role for lithium in the prophylaxis of manic-depressive illness, in spite of a lot of doubts and opposition (especially among the British psychiatrists). He published well over 500 articles on lithium. He remained an unfettered defender of lithium's use during the attacks on lithium, doubts about its efficacy, reports of its toxicity and possible teratogenicity. He has published excellent summaries and anniversary, articles on lithium treatment.[sup] [5] In the recent era, when many new agents are being proposed (mainly by the pharmaceutical industry) as stabilizers, some may ask, what, there are other, easier to use mood True, we have many other medications, such as valproic acid, carbamazepine, and several other anticonvulsants and antipsychotics, used as anti-manic agents or mood stabilizers. However, as Schou[sup] [5] and others pointed out, the prophylactic effect of these so called mood stabilizers remains either weak or missing. Lithium remains a unique agent, the gold standard among the so called mood stabilizers. As Bauer and Mitchner[sup] [6] stated in their review, the evidence supports a role for lithium as a first-line agent for the treatment of manic-depressive (bipolar) disorder. …

Comparison of carbamazepine and lithium in treatment of bipolar disorder: A systematic review of randomized controlled trials

To review data from randomized controlled trials (RCTs) assessing the comparative efficacy of carbamazepine and lithium in treatment of acute manic and maintenance phase of bipolar disorder (BD). RCTs were identified through a search strategy that included: electronic databases, reference cross-checking, hand search of non-indexed publications, and book chapters on the treatment of BD comparing carbamazepine with lithium. Outcomes investigated were antimanic effect, trial withdrawal, relapse, hospitalization, need for rescue medication, and presence of adverse effects. Selection of studies and data analysis were performed independently by authors. Whenever possible, data from trials were combined through meta-analyses. Relative risks (RR) were estimated for dichotomous data. In acute mania, carbamazepine was similar to lithium on the following outcomes: trial withdrawal due to adverse effects, number of participants with at least one adverse effect, improvement in the Clinical Global Impression (CGI). In acute mania, carbamazepine was associated with fewer trial withdrawals. In maintenance treatment, carbamazepine was similar to lithium in relapses and hospitalization, but there were fewer trial withdrawals due to adverse effects on lithium. This review suggests that carbamazepine might be comparable to lithium in terms of efficacy and safety, and therefore a valuable option in the treatment of both manic and maintenance phases.

The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs

Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150mg/kg, i.p.), tamoxifen (1.0mg/kg, i.p.) and chelerythrine (1μg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0mg/g) and higher (6.0mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.

Psychotropic Medications for Patients With Bipolar Disorder in the United States: Polytherapy and Adherence

Psychotropic Medications for Patients With Bipolar Disorder in the United States: Polytherapy and Adherence

Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of Mania

Considerable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in mania-associated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site GluN1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as in behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro- and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.

A Double-Blind, Randomized, Placebo-Controlled 4-Week Study on the Efficacy and Safety of the Purinergic Agents Allopurinol and Dipyridamole Adjunctive to Lithium in Acute Bipolar Mania

The therapeutics for bipolar disorders are still far from adequate, and new options with improved effectiveness, safety, and tolerability in a wide range of patients are necessary. Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders. This study aimed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania. A randomized, placebo-controlled, double-blind study was performed in adult inpatients (N = 180) with a DSM-IV-TR diagnosis of bipolar I disorder, current episode manic with or without psychotic features (rapid cyclers and mixed episodes were not included). No antipsychotic agent was used during the study. Subjects were given fixed oral doses of either allopurinol 600 mg/day (N = 60), dipyridamole 200 mg/day (N = 60), or placebo (N = 60) added to lithium for 4 weeks. Subjects were rated at baseline and days 7, 14, 21, and 28 using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. The study was conducted between September 2003 and September 2006. Allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (p < .001) and day 28 (p = .003) compared with placebo using a linear model analysis (d = 0.32, 95% CI = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo (p = .008). Lithium showed a significant antimanic efficacy even in the placebo group. Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group (p < .001). Allopurinol is clinically effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania, especially for those presenting tolerability and safety issues with antipsychotics. The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder. Further placebo-controlled studies with allo-purinol compared with standard mood stabilizers in mania and maintenance are warranted. clinicaltrials.gov Identifier: NCT00560079.

Antimanic potency of typical neuroleptic drugs and affinity for dopamine D2 and serotonin 5-HT2A receptors — a new analysis of data from the archives and implications for improved antimanic treatments

Datasets of antimanic potency ratings and receptor-binding affinities [inhibition constants (K(i))] at dopamine D2 and serotonin 5-HT2A brain receptors were accessed from published literature for a large series (n = 24) of typical neuroleptic drugs, many of which are now obsolete and unobtainable. There was a strong positive association between antimanic potency and affinity for D2 receptors, in support of a 'dopamine-blockade hypothesis' of antimanic drug action. Taking the series of neuroleptics as a whole, there was no association between antimanic potency and affinity for 5-HT2A receptors. Despite this, within a subsample of typical neuroleptics with low affinity for D2 receptors resembling new generation atypical antipsychotics, a positive association between antimanic potency and affinity for 5-HT2A receptors emerged. This suggests that blockade of brain 5-HT2A receptors plays at least a subsidiary role in the antimanic effects of some typical neuroleptics. Other considerations also suggest that combining drugs to achieve high affinity for and blockade of both dopamine D2 receptors and serotonin 5-HT2A receptors, possibly with additional direct or indirect stimulation of postsynaptic 5-HT1A receptors, might maximize antimanic efficacy.

Mania: a Rational Neurobiology

A cohesive picture has emerged over the last decade regarding the pathophysiology and treatment of bipolar disorder, a serious mental disorder that cycles between mania and depression. Mania is associated with overactive PKC intracellular signaling, and recent genome-wide association studies of bipolar disorder have implicated an enzyme that reduces the activation of PKC. Overactive PKC signaling in the prefrontal cortex may explain many of the symptoms of mania. Functional imaging studies have shown reduced activity in the right prefrontal cortex during the manic state. Dysfunction of the right prefrontal cortex is known to lead to a disinhibited profile, including poor impulse control, risk-taking, distractibility, poor sustained attention and delusions, which resemble the symptoms of mania. Structural imaging studies have further shown a loss of prefrontal volume in untreated patients with bipolar disorder. This loss of function and gray matter in the prefrontal cortex may arise from abnormal signaling cascades, notably PKC signaling. Studies in animals have shown that elevated PKC activity markedly and rapidly impairs the functioning of the prefrontal cortex, providing a link to the the loss of prefrontal regulation of thought and emotion during the manic state. Sustained elevation in PKC signaling may also lead to loss of gray matter in the prefrontal cortex, which can be protected by PKC inhibitors. Importantly, the current mainstays in the treatment of mania, lithium (a monovalent cation) and valproate (a small fatty acid), indirectly inhibit PKC. Proof-of-principle studies with the antiestrogenic PKC inhibitor tamoxifen have shown rapid antimanic effects. Recent evidence suggests that lithium may also protect prefrontal gray matter in patients. These data indicate that new, direct PKC inhibitors are needed as potential new treatments for bipolar disorder.

In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity

JZP-4 is a potent calcium and sodium channel blocker, which is currently being evaluated in patients as an anticonvulsant and mood stabilizer. In the current studies, JZP-4 was evaluated in a variety of animal models for anticonvulsant, antimania and antidepressant activity. In the mouse and rat maximal electroshock models, JZP-4 was slightly more potent than LTG. In the mouse pentylenetetrazole induced seizures model, JZP-4 was approximately twice as potent as lamotrigine in prolonging the time to clonus. In the mouse 6-Hz model for drug resistant or refractory epilepsy, JZP-4 had potent anticonvulsant activity at all current intensities, whereas LTG was active at only the lowest current intensity. In the mouse amphetamine-chlordiazepoxide model for antimanic effects, JZP-4, but not LTG, produced dose-related and significant effects at 3 and 10 mg/kg i.p. In the rat forced swim model of antidepressant activity, JZP-4 (30 mg/kg i.p.) produced a significant reduction in immobility and an increase in climbing behavior. LTG (30 mg/kg i.p.) produced similar effects but these effects did not achieve statistical significance. The specificity of this antidepressant response was confirmed in the rat locomotor test. In this test, JZP-4 produced dose-related and significant reductions in locomotor activity, indicating that it was not a CNS stimulant. LTG produced no significant effects in the rat locomotor test. The studies have demonstrated that JZP-4 has greater potency and efficacy than LTG in models of refractory epilepsy, antidepressant activity and antimania activity. The variance between the effects of LTG and JZP-4 may be related to the greater potency at sodium channels or the additional pharmacological actions of JZP-4 on calcium channels.

Valproate-Induced Subclinical Hypothyroidism

Back to table of contents Previous article Next article LETTERFull AccessValproate-Induced Subclinical HypothyroidismPallavi Rao M.D.D.S., M.D.Shanker Madhav Natu M.Sc., Ph.D.Madhu Mati Goel M.B.B.S., M.D.Bashir Ali M.Sc., Ph.D.,Pallavi Rao M.D.D.S., M.D.Search for more papers by this authorShanker Madhav Natu M.Sc., Ph.D.Search for more papers by this authorMadhu Mati Goel M.B.B.S., M.D.Search for more papers by this authorBashir Ali M.Sc., Ph.D.Search for more papers by this author,Published Online:1 Jan 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Drug-induced hypothyroidism has been well established in the literature with drugs like lithium, iodine, and amiodarone. We report a rare case of subclinical hypothyroidism in a patient on long-term valproate therapy. A 30-year-old patient undergoing treatment for manic-depressive bipolar disorder presented with complaints of increasing fatigue and weakness. He was on sodium valproate and olanzapine therapy for 8 years before his clinical presentation. His laboratory findings revealed a raised thyrotropin (TSH) of 27.61 microIU/ml (normal range=4–7 microIU/ml) with normal T3 and T4, on two consecutive occasions. His liver function tests showed a raised SGPT (60U/liter). His renal function tests and basic hematological parameters were within normal limits. Subsequent tests for antithyroid antibodies were negative. There was no past history or family history of any thyroid disease. Subclinical hypothyroidism is manifested by raised TSH with normal T3 and T4 levels. The prevalence of subclinical hypothyroidism is approximately 14% and is more frequently observed in females. 1 The main causes of hypothyroidism are autoimmune disorders, inflammation, iodine deficiency, drugs, radio ablated thyroid gland, post surgical resection, and pituitary disorders. Patients with subclinical hypothyroidism may occasionally present with signs and symptoms of clinically apparent hypothyroidism, such as fatigue, weight gain, and dry skin. The association of hypothyroidism with drugs like lithium, amiodarone, and iodine is well established in the literature. Antiepileptic drugs, however, have been recently added to the list. Sodium valproate is commonly used in the treatment of epilepsy and bipolar disorder. It acts by destroying γ-aminobutyric acid (GABA) antagonist thereby increasing the levels of GABA, which is said to have an antimanic effect. The well-known side effects of valproate therapy are weight gain, dyspepsia, headache, and hepatotoxicity. Studies in children undergoing long-term valproate therapy have shown a significantly higher level of TSH compared to controls. 2 Higher levels of TSH, with normal T3 and T4, were also seen in girls undergoing valproate monotherapy. 3 Contradictory to this, some reports suggest that though antiepileptic drugs like carbamazepine and phenytoin have been found to induce hypothyroidism—due to their hepatic enzyme induction properties which lead to increased clearance of thyroid hormones—valproate did not seem to have the same effect on thyroid function as it was not a hepatic enzyme inducer. 4As our patient presented with excessive fatigue, we evaluated his thyroid function tests, which revealed a subclinical hypothyroid state. Increased SGPT levels noted in the patient may be due to hepatotoxic potential of valproate. The patient had no history of radioiodine therapy or any surgical procedure which might have accounted for this clinical state. The patient had negative antithyroid antibody screens ruling out autoimmune causes. As there was no evidence in the literature to support the role of olanzapine in induction of hypothyroidism, we attribute the hypothyroid state of our patient to long-term valproate therapy.This case report highlights the importance of routine thyroid function tests in patients undergoing long-term valproate therapy, which may lead to early detection of subclinical hypothyroid state and thereby prevent subsequent complications.King George Medical University, Lucknow, IndiaReferences1 . Díez JJ, Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 2004; 89:4890–4897Google Scholar2 . Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, et al: Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia 1999; 40:1761–1766Google Scholar3 . Vainionpaa LK, Mikkonen K, Rattya J, et al: Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication. Epilepsia 2004; 45:197–203Google Scholar4 . Isojarvi JI, Pakarinen AJ, Myllyla VV: Thyroid function with antiepileptic drugs. Epilepsia 1992; 33:142–148Google Scholar FiguresReferencesCited byDetailsCited BySevere fatigue due to valproate-induced hypothyroidism in a case of bipolar disorder5 September 2020 | Annals of General Psychiatry, Vol. 19, No. 1Effect of antiepileptic drugs on the thyroid gland in adult albino ratsThe Egyptian Journal of Histology, Vol. 38, No. 1 Volume 20Issue 1 Winter, 2008Pages 111-112 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008

Epigenetics in mood disorders.

Depression develops as an interaction between stress and an individual's vulnerability to stress. The effect of early life stress and a gene-environment interaction may play a role in the development of stress vulnerability as a risk factor for depression. The epigenetic regulation of the promoter of the glucocorticoid receptor gene has been suggested as a molecular basis of such stress vulnerability. It has also been suggested that antidepressive treatment, such as antidepressant medication and electroconvulsive therapy, may be mediated by histone modification on the promoter of the brain-derived neurotrophic factor gene. Clinical genetic studies in bipolar disorder suggest the role of genomic imprinting, although no direct molecular evidence of this has been reported. The role of DNA methylation in mood regulation is indicated by the antimanic effect of valproate, a histone deacetylase inhibitor, and the antidepressive effect of S-adenosyl methionine, a methyl donor in DNA methylation. Studies of postmortem brains of patients have implicated altered DNA meA methylation of the promoter region of membrane-bound catechol-O-methyltransferase in bipolar disorder. An altered DNA methylation status of PPIEL (peptidylprolyl isomerase E-like) was found in a pair of monozygotic twins discordant for bipolar disorder. Hypomethylation of PPIEL was also found in patients with bipolar II disorder in a case control analysis. These fragmentary findings suggest the possible role of epigenetics in mood disorders. Further studies of epigenetics in mood disorders are warranted.