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PubMed2004

Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression.

Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic (but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium- or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Animals↗
PubMed1993

Depressive mania associated with nonresponse to antimanic agents.

Of 39 patients consecutively admitted for the treatment of primary mania, 21 (53.8%) simultaneously met the Research Diagnostic Criteria for major depressive disorder ("mixed" or "depressive" mania). Only nine (42.9%) of the 21 patients with depressive mania responded to antimanic agents. In contrast, 16 (88.9%) of the 18 patients with pure mania responded to these drugs. This finding is consistent with previous reports suggesting that the mixed state is a virulent form of mania.

Adult↗
PubMed2003

Structurally dissimilar antimanic agents modulate synaptic plasticity by regulating AMPA glutamate receptor subunit GluR1 synaptic expression.

A growing body of data from clinical and preclinical studies suggests that the glutamatergic system may represent a novel therapeutic target for severe recurrent mood disorders. Since synapse-specific glutamate receptor expression/localization is known to play critical roles in synaptic plasticity, we investigated the effects of mood stabilizers on AMPA receptor expression. Rats were treated chronically with lithium or valproate, hippocampal synaptosomes were isolated, and GluR1 levels were determined. Additionally, hippocampal neurons were prepared from E18 rat embryos and treated with lithium or valproate. Surface expression of GluR1 was determined using a biotinylation assay, and double-immunostaining with anti-GluR1 and anti-synaptotagmin antibodies was used to determine synaptic GluR1 levels. The AMPA receptor subunit GluR1 expression in hippocampal synaptosomes was significantly reduced by both chronic lithium and valproate. Overall, these studies show that AMPA receptor subunit GluR1 is a common target for two structurally highly dissimilar, but highly efficacious, mood stabilizers, lithium and valproate. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Animals↗
PubMed1996

The relationship between antimanic agent for treatment of classic or dysphoric mania and length of hospital stay.

BACKGROUND: This retrospective study was conducted to evaluate the relationship between the mood-stabilizing agents lithium, carbamazepine, and divalproex sodium and time course of drug response as measured by length of hospital stay. METHOD: Seventy-eight patients were evaluated. Discharge date and length of hospitalization were obtained by review of the dictated discharge summary by investigators who were blind to medication status. Drug choice, including blood levels, was then identified as well as any adjunctive treatment. Statistical evaluation (SAS software) of time to improvement was conducted using nonparametric survival models. Possible confounding variables were assessed by parametric survival regression models and proportional hazards models. RESULTS: The individual survival curves of four major antimanic treatment groups revealed a significant difference by the second week of hospitalization in the divalproex sodium and the lithium/carbamazepine combination groups as compared with the lithium or carbamazepine groups (chi 2 = 13.83, df = 3, p = .003). The mean +/- SD length of stay was approximately 40% shorter for the divalproex sodium (10.2 +/- 2.0 days) and the lithium/carbamazepine combination (11.7 +/- 2.1 days) groups compared with the lithium alone (17.6 +/- 1.0 days) and the carbamazepine alone (18.1 +/- 3.0 days) groups. Regression analysis of possible confounding variables including adjunctive treatment (benzodiazepines and neuroleptics), severity of illness (number of years ill and previous hospitalizations), and discharge date revealed no statistically significant effect. CONCLUSION: Shortcomings of our study include those inherent in the design of a non-randomized, small naturalistic study and retrospective chart review. Our study does, however, suggest different drug response rates for the treatment of classic and dysphoric mania and warrants further controlled investigation.

Adult↗
PubMed1996

Health-economic implications of the onset of action of antimanic agents.

BACKGROUND: Three medications, lithium, valproate, and carbamazepine, have been shown to be effective in the treatment of acute mania in randomized, controlled clinical trials. Additional research over the past decade has provided data regarding potential differences between these medications according to their time course of onset and clinical predictors of response in acute mania. These differences have potential impact on both the choice of medication and the health-economics of the treatment of acute mania. METHOD: Published reports regarding the time course of onset, clinical factors associated with response, and health-economic impact of the treatment of acute mania with lithium, valproate, and carbamazepine were reviewed (PAPERCHASE data base, 1966 to present, terms: bipolar disorder, drug treatment, lithium, valproate, and carbamazepine). RESULTS: Valproate, when administered via an oral loading dosage, may have a more rapid onset of action than lithium and carbamazepine. Preliminary data suggest that specific clinical factors associated with response differ between the three medications. Health-economic studies suggest that treatment of acute mania with valproate may be associated with greater cost savings due to shorter lengths of hospital stay, particularly in patients with mixed mania and rapid cycling. Patients treated with the combination of carbamazepine and lithium also had reduced hospital lengths-of-stay in one study. Lithium may have greater cost savings in patients with classic mania. CONCLUSION: Preliminary data from studies reviewed suggest that important differences exist between lithium, valproate, and carbamazepine in their time course of onset and factors associated with response in the treatment of patients with acute mania. These differences may also impact the cost savings associated with treatment with these agents.

Bipolar Disorder↗
PubMed2005

Caffeine and psychiatric medication interactions: a review.

Caffeine can cause or worsen psychiatric symptoms but also has the potential to interact with many psychiatric medications. This article provides a literature review regarding interactions between caffeine and psychiatric medications. Caffeine is metabolized by the CYP1A2 enzyme and also acts as a competitive inhibitor of this enzyme. Thus, caffeine can interact with a wide range of psychiatric medications, including antidepressant agents, antipsychotic agents, antimanic agents, antianxiety agents, and sedative agents. These interactions may lead to caffeine-related or medication-related side effects that may complicate psychiatric treatment. By recognizing this potential, along with educating the patient, and utilizing a tapering approach, prevention of caffeine interactions is achievable.

Anti-Anxiety Agents↗
PubMed2001

Definition, evaluation, and management of treatment refractory mania.

Treatment refractory mania is a common clinical problem. Unfortunately, the treatment of acute mania refractory to standard antimanic and mood-stabilizing medications has not been well studied. This review will discuss the definition, evaluation, and differential diagnosis of treatment refractory mania; the definition of an adequate treatment trial for acute mania; the identification of predictors of treatment response; and clinical trials in treatment refractory mania. Computerized searches of the medical literature regarding treatment refractory mania were undertaken using Paperchase (1966-2001), and bibliographies of all articles identified were reviewed to identify all relevant case reports, case series, clinical trials, and methodologic and phenomenologic reports. Operational definitions of treatment refractory mania were proposed based on sequential nonresponse to adequate trials of antimanic agents. The average time of onset of antimanic agents studied in randomized trials was 1 to 2 weeks. Clinical tools for assessing treatment response retrospectively and prospectively appear to have an important role in managing medication treatment in patients with bipolar disorder. Relatively few reliable predictors of treatment response to established antimanic agents have been identified. However, these predictors represent important factors in treatment selection to minimize the probability of nonresponse. Very few randomized, controlled trials of antimanic agents have been conducted in patients with treatment refractory mania. Field testing of treatment algorithms and systematic collection of data from naturalistic treatment studies should provide much-needed data regarding the efficacy of antimanic agents in treatment refractory mania.

Antimanic Agents↗
PubMed1999

Methodological considerations for the development of new treatments for bipolar disorder.

Lithium has been the drug of choice in treating bipolar disorder for 50 years and, therefore, patterns of response associated with its use define what we expect from treatment. Although efforts to establish some other agents as antimanic have been successful, it is difficult to assess their overall efficacy in relation to that of lithium without a better understanding of inclusion/exclusion criteria, subtypes, definitions of remission, relapse and recurrence, and duration of study. All of these factors need to be carefully addressed to identify the most important clinical targets for new drug development. Additional relevant information emerges from studies on combinations of mood stabilisers, efficacy of antimanic agents in different patient populations, analysis of rates of drop-out, non-compliance, suicide, drug abuse, and discontinuation especially with long-term treatment. Agents other than lithium that are effective in the acute phase treatment are still not well characterised as mood stabilisers. New agents need to be evaluated in the context of long-term treatment and the targeting of specific components of the syndrome beyond mania.

Affect↗
PubMed2002

The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues.

BACKGROUND: Although symptoms of anxiety as well as anxiety disorders commonly occur in patients with bipolar disorder, the pathophysiologic, theoretical, and clinical significance of their co-occurrence has not been well studied. METHODS: The epidemiological and clinical studies that have assessed the overlap of bipolar and anxiety disorders are reviewed, with focus on panic disorder and obsessive-compulsive disorder (OCD), and to a lesser extent, social phobia and post-traumatic stress disorder. Potential neural mechanism and treatment response data are also reviewed. RESULTS: A growing number of epidemiological studies have found that bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population. Clinical studies have also demonstrated high comorbidity between bipolar disorder and panic disorder, OCD, social phobia, and post-traumatic stress disorder. Psychobiological mechanisms that may account for these high comorbidity rates likely involve a complicated interplay among various neurotransmitter systems, particularly norepinephrine, dopamine, gamma-aminobutyric acid (GABA), and serotonin. The second-messenger system constituent, inositol, may also be involved. Little controlled data are available regarding the treatment of bipolar disorder complicated by an anxiety disorder. However, adequate mood stabilization should be achieved before antidepressants are used to treat residual anxiety symptoms so as to minimize antidepressant-induced mania or cycling. Moreover, preliminary data suggesting that certain antimanic agents may have anxiolytic properties (e.g. valproate and possibly antipsychotics), and that some anxiolytics may not induce mania (e.g. gabapentin and benzodiazepines other than alprazolam) indicate that these agents may be particularly useful for anxious bipolar patients. CONCLUSIONS: Comorbid anxiety symptoms and disorders must be considered when diagnosing and treating patients with bipolar disorder. Conversely, patients presenting with anxiety disorders must be assessed for comorbid mood disorders, including bipolar disorder. Pathophysiological, theoretical, and clinical implications of the overlap of bipolar and anxiety disorders are discussed.

Antidepressive Agents↗
PubMed2006

Polytherapy in bipolar disorder.

Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.

Antidepressive Agents↗
PubMed2005

Treatment guidelines for bipolar disorder: a critical review.

INTRODUCTION: The development of treatment guidelines emerged as an important element so as to standardize treatment and to provide clinicians with algorithms, which would be able to carry research findings to the everyday clinical practice. MATERIAL AND METHOD: The MEDLINE was searched with the combination of each one of the key words 'mania', 'manic', 'bipolar', 'manic-depression', 'manic-depressive' with 'treatment guidelines'. RESULTS: The search was updated until March 1st, 2004 and returned 224 articles. Twenty-seven papers concerning the publication of treatment algorithms were traced. DISCUSSION: Despite supposedly being evidence-based, guidelines for the treatment of bipolar disorder vary significantly across committees or working groups. Overall, however, at the first stage of the mania/hypomania algorithm, monotherapy with lithium, divalproex sodium or olanzapine is generally recommended. At latter stages combination therapy is strongly recommended. It is clearly stated that in bipolar depression antidepressants should be used only in combination with antimanic agents in order to avoid switching of phases. During the maintenance phase all patients should receive antimanic agents, while some may need the addition of antidepressants. The most recent guidelines emphasize the use of atypical antipsychotics for mania and lamotrigine for depression. The main problem with guidelines is that they are rapidly outdated and that the evidence base relies mainly on registration monotherapy trials that hardly reflect treatment in routine clinical conditions. CONCLUSION: Treatment guidelines may be useful to avoid non-evidence-based treatment decisions, but they are quickly out-of-date and may not fully apply to the clinical setting. The more recent guidelines point the value of atypical antipsychotics, lithium, and valproate in the treatment of mania; the role of lithium, lamotrigine, and olanzapine as options for maintenance therapy; and the scarcity of options for the treatment of bipolar depression. Psychoeducation is also supported by most guidelines as an adjunctive treatment.

Algorithms↗
PubMed1993

Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems.

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or alpha-methyl-p-tyrosine, but not by 5-HT depletion with p-chlorophenylalanine. These data suggest that lithium enhances 5-HT1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [3H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT1A receptor down-regulation and unaltered 5-HT1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Rapid titration of mood stabilizers predicts remission from mixed or pure mania in bipolar patients.

BACKGROUND: Recent investigations have suggested that the antimanic agents divalproex sodium and carbamazepine may each hasten hospital discharge and be especially beneficial in treating mixed-state mania. This study retrospectively compared the time to remission for pure versus mixed manic bipolar inpatients who were taking lithium, divalproex, or carbamazepine, or their combination, under naturalistic conditions. METHOD: Records were reviewed for 120 bipolar inpatients from 1991 to 1995. Research DSM-III-R diagnoses of pure or mixed mania were assigned along standardized guidelines. Data were obtained on daily symptoms, medication doses, and blood levels. Weekly improvement was evaluated by Kaplan-Meier survival analysis of Clinical Global Impressions scale scores. Variables associated with "remission" versus "nonremission" were examined by logistic regression. RESULTS: Mixed mania (N = 70) was more common than pure mania (N = 50). No significant differences were observed in the time to remission for mixed or pure manic bipolar patients who took lithium compared with those who took divalproex or carbamazepine. In patients who remained symptomatic with lithium as a single-agent mood stabilizer despite therapeutic serum lithium levels, the addition of a second mood stabilizer led to rapid symptom improvement. Among all medication subgroups, the speed with which patients achieved therapeutic blood levels of any of these agents significantly affected the time to remission. CONCLUSION: Mixed manic bipolar patients taking lithium, divalproex, or carbamazepine under naturalistic conditions remit at comparable rates. Those failing to respond to single-agent mood stabilizers often receive combinations of mood stabilizers. However, delays in optimizing a medication regimen may attenuate short-term outcome, regardless of the mood stabilizer selected. Rapid achievement of therapeutic blood levels of any antimanic agent appears to be strongly related to swift symptom remission.

Adult↗
PubMed2000

A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency.

Both lithium and valproate have been used in the treatment of manic-depressive illness with very limited understanding of their therapeutic mechanism of action. Recent literature suggests that blocking of potassium channels may be a common therapeutic mechanism of many antidepressant agents. To determine whether the commonly used antimanic agents could prevent potassium efflux-induced cell damage and apoptosis and the underlying mechanisms, we treated SH-SY5Y human neuroblastoma cells with the potassium ionophore, valinomycin (2-100 microM) and observed cell shrinkage, mitochondria damage, a significant increase in of lactate dehydrogenase (LDH) activity and caspase-3 protein expression. Cells treated with lithium (0.5-3 mM) or valproate (0.07-1.4 mM) alone produced no apoptotic morphological and biochemical changes while both mood stabilizers pretreatment reduced or prevented the apoptotic morphological changes. However, valinomycin-induced caspase-3 elevation was only prevented by lithium pretreatment while both lithium and valproate attenuated valinomycin-induced LDH release. Our results suggest that lithium and valproate share a common neuroprotective action against potassium efflux-induced cell apoptosis with different mechanisms.

Antimanic Agents↗
PubMed2002

[Atypical antipsychotics in the treatment of bipolar affective disorders].

Antipsychotics are commonly used in the treatment of bipolar affective disorder. The use of conventional antipsychotic agents, though effective as antimanic agents, is associated with a number of limitations such as their acute side effect profile and their unsufficient mood stabilizing activity. In addition, exposure to conventional neuroleptics poses a risk for the development of tardive dyskinesia, especially in mood disorder patients. Growing evidence suggests that the novel, so-called atypical neuroleptics may offer a number of advantages in the treatment of bipolar disorder, including their thymoleptic activity and minimal risk for acute and long-term extraypyramidal symptoms. Clinical experience with clozapine and olanzapine as mood stabilizers suggests greater antimanic than antidepressant properties, while risperidone may have greater antidepressant properties with some liability for triggering or exacerbating mania. The mood stabilizing properties of further atypical drugs are currently under investigation. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder. We also present an overview concerning potential pharmakokinetic interactions based on the cytochrome P450 enzyme system when antipsychotics are combined with other mood stabilizing compounds. In conclusion, atypical antipsychotics should come to play an increasingly important role in the acute and long-term management of bipolar disorder, but there is a clear need for further controlled trials in this indication.

Anticonvulsants↗
PubMed1998

Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics.

Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.

Antidepressive Agents↗
PubMed1998

Divalproex sodium for impulsive aggressive behavior in patients with personality disorder.

OBJECTIVE: Divalproex sodium, an anticonvulsant and antimanic agent, has recently been studied for its antiaggressive effects in patients with brain injuries, dementia, and borderline personality disorder. Since patients with other personality disorders also exhibit impulsive aggressive behavior, we conducted a preliminary open-label trial of divalproex sodium as a treatment for irritability and aggression in patients with a variety of personality disorders. METHOD: Ten patients meeting DSM-IV criteria for at least one personality disorder were treated with divalproex sodium in an 8-week open clinical trial. All patients had failed a trial of a selective serotonin reuptake inhibitor (SSRI). Divalproex sodium was increased as tolerated using a flexible dosing schedule. Clinician ratings for impulsive aggressive behavior and irritability were made every 2 weeks using the modified Overt Aggression Scale (OAS-M). RESULTS: Six of 8 completers reported significant decreases in irritability (p = .003) and impulsive aggressive behavior (p = .019). For the entire sample, improvement on OAS-M irritability and overt aggression scores was noted by the end of 4 weeks and continued to occur through week 8. CONCLUSION: This study suggests that divalproex sodium is an effective treatment for impulsive aggressive behavior in some patients with personality disorder who fail to respond to other antiaggressive agents (i.e., SSRIs). Controlled studies are needed to determine which patients are most likely to benefit from divalproex sodium and to evaluate the differential effectiveness of various agents in reducing impulsive aggressive behavior.

Adult↗