Long-term treatment of bipolar disorder with lamotrigine.
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Bipolar depression is as debilitating as mania in bipolar disorder, but the treatment of bipolar depression has historically received less attention. To date, there is no mood stabilizer (liberally defined as a medication that decreases episode severity, duration, or frequency in one phase of bipolar illness without producing a negative effect in other phases) that demonstrates similar efficacy in both the depressive and the manic phases of bipolar disorder. However, bipolar depression--which is prevalent, sometimes chronic, and associated with a low quality of life and a high risk of suicide--must be addressed as energetically as mania. Recent research into the long-term treatment of bipolar disorder has raised several questions about the generalizability of early lithium studies, as a result of these studies' designs. Researchers conducting more recent studies of mood stabilizers in the long-term treatment of bipolar disorder have attempted to clarify their results by, for example, performing survival analyses of the data. Until pharmacotherapy has been found that is equally efficacious in the treatment of both manic and depressive episodes in bipolar disorder, the use of combination therapy to manage bipolar disorder is advised. Lithium and divalproex sodium remain the first-line treatments for mania. Lamotrigine has been found to have acute efficacy in treating episodes of bipolar depression without increasing cycling or provoking a switch into mania, as well as a long-term role in delaying relapse and recurrence of depressive episodes.Keywords:
Mood stabilizer
Depression
Bipolar II disorder
Bipolar I disorder
Divalproex
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Bipolar depression is the underrecognized and unappreciated phase of bipolar disorder. Nevertheless, bipolar depression is responsible for much of the morbidity and mortality associated with the disorder. Depressive symptoms are far more prevalent than hypomanic or manic symptoms in bipolar patients, and they are associated with a heavier burden of illness, including reduced functioning, increased risk of suicidal acts, and high economic costs. Because most patients with bipolar disorder present with depression, misdiagnoses of major depressive disorder are common, even typical. Comorbid psychiatric disorders are also prevalent and may obscure the diagnosis and complicate treatment strategies. Depressed patients should be carefully assessed for manic or hypomanic symptoms to help reveal possible bipolar disorder. In addition to evaluation of psychiatric symptoms, a close examination of family history, course of illness, and treatment response will aid the clinician in making an accurate diagnosis. Treatment of acute depression in bipolar patients may require therapy combining agents such as lithium, divalproex, lamotrigine, carbamazepine, and atypical antipsychotics or using such agents in combination with an anti-depressant. Olanzapine/fluoxetine combination is the only medication currently approved for the treatment of bipolar depression. Antidepressant monotherapy should not be used, because there is evidence that such treatment increases the risk of switching into mania/hypomania and could induce treatment-refractory conditions such as mixed or rapid-cycling states. Maintenance therapy will be required by most patients, since discontinuation of mood stabilizers or antidepressants frequently leads to relapses in depressive symptoms. Prompt diagnosis and the use of specific therapeutic agents with evidence of efficacy may help reduce the disease burden associated with bipolar depression.
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To the Editor: A prior shorter mnemonic (CALM, published previously in the Companion1) helped clinicians organize the pharmacologic treatment options for bipolar disorder. The current mnemonic CALM SEA incorporates a review of biorhythm and endocrine issues, as well as an image of the goal.
C = Control Cycling, starting with manic and mixed symptoms, especially insomnia, irritability, agitation, impulsivity, and anxiety, as these disrupt work situations and social supports (burn bridges), and even subsyndromal mixed mania has been associated with increased risk for suicidal behavior.2,3 Uncontrolled cycling renders patients’ lives chaotic, unpredictable, and unmanageable.
A = Antidepressants. Use conventional antidepressants (preferential unipolar antidepressants4) sparingly and selectively beyond 10 weeks. Adjunctive antidepressants have demonstrated benefit beyond 10 weeks of treatment in only 15% to 20% of bipolar patients, and only in the Stanley Foundation Bipolar Network studies.4–8 Two important recent Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) studies9,10 showed no separation of adjunctive antidepressants from adjunctive placebo. Further, another STEP-BD study with 1,742 patients followed for up to 1 year showed that “patients who received antidepressants were 3.8 times as likely to experience rapid cycling,” ie, 4 or more mood episodes (P = .001), and “2.0 times as likely to have 2 or 3 episodes (P = .0001) . . . compared to patients who did not receive antidepressants.”11(p374) For longer term use, consider preferential bipolar antidepressants,4 eg, lamotrigine, quetiapine, lithium, or olanzapine,4,12 with appropriate monitoring.
L = Longitudinal/long-term view. A longitudinal/long-term view of mood episodes over months to years is pivotal to making the diagnosis of bipolar disorder in the first place, to understanding the patient's intrinsic or baseline pattern of mood cycling, and to accurately gauging the patient's response to treatment.
M = Mood stabilizers, especially lithium, divalproex, and carbamazepine, remain the core building blocks of effective bipolar disorder regimens.13 Lamotrigine provides an extremely helpful floor against recurrent depression but lacks robust antimanic coverage.4,14
S = Sleep. Consistent, regular-onset, full-duration, uninterrupted, restorative sleep is an essential component of any recovery from bipolar disorder and can generally be reestablished using primarily the sedative and antimanic properties of lithium, divalproex, or carbamazepine, with or without atypical antipsychotics. Antidepressants may aggravate insomnia,15 and gradual antidepressant taper over months often relieves it.16,17
E = Endocrine/metabolic hot spots can be remembered as TSH:
T-Thyroid augmentation may relieve cycling or depression18,19 with even mild hypothyroidism, or even euthyroid state. Monitor TSH periodically, especially in lithium-treated patients.
S-Steroid treatments may trigger mood episodes, usually mania or mixed states.
H-Hormonal shifts (especially in women), such as puberty/menarche, postpartum, and perimenopause/menopause, may initiate mood episodes.
A = Activity. Regular activity, exercise, and social activity, including “‘social zeitgebers,’ ie, persons, social demands, or tasks that set the biological clock,”20(p948) comprise the important complement of regular sleep in maintaining a regular sleep-wake cycle and “lifestyle regularity,”21 indispensable components of recovery.20–22 Therefore, it may be advantageous to explain this to patients and their family or support system so that they can structure activity and social interaction as part of their recovery.
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Abstract As bipolar disorder is a recurrent illness over the lifetime of the patient, a central aspect of its successful treatment is the prevention of new mood episodes rather than simply the stabilization of acute manic or depressive episodes. For decades lithium was the only effective medication available for this purpose. However, not all patients responded to lithium, particularly those with a rapid cycling course of illness (four or more affective episodes per year) or mixed states (meeting criteria for depressive and manic states simultaneously). Over the last 15 years or so, fortunately, many new medications have emerged to greatly expand therapeutic options for our patients. Anticonvulsants such as valproate, carbamazepine, and lamotrigine have all received FDA approvals for treatment of bipolar mood states. This article summarizes the roles that lithium and several anticonvulsants play in the current treatment of mood disorders, with attention to their mechanism of action, indications, dosing, and side effects.
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Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990 s, form the second generation of such drugs. The response of patients with bipolar disorder to mood stabilizers has different levels of magnitude. About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The main phenotype of the response to mood stabilizers is a degree of prevention against recurrences of manic and depressive episodes during long-term treatment. The most specific scale in this respect is the so-called Alda scale, where retrospective assessment of lithium response is scored on a 0-10 scale. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The studies on the mechanisms of action of lithium and on the neurobiology of bipolar disorder have led to the identification of a number of candidate genes. The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers (phosphatidyl inositol [PI], cyclic adenosine-monophosphate [cAMP] and protein kinase C [PKC] pathways), substances involved in neuroprotection (brain-derived neurotrophic factor [BDNF] and glycogen synthase kinase 3-β [GSK-3β]) and a number of other miscellaneous genes. There are no published pharmacogenomic studies of mood stabilizers other than lithium, except for one study of the X-box binding protein 1 (XBP1) gene in relation to the efficacy of valproate. In recent years, a number of genome-wide association studies (GWAS) in bipolar disorders have been performed and some of those have also focused on lithium response. They suggest roles for the glutamatergic receptor AMPA (GRIA2) gene and the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene in long-term lithium response. A promise for better elucidating the genetics of lithium response has been created by the formation of the Consortium on Lithium Genetics (ConLiGen) to establish the largest sample, to date, for the GWAS of lithium response in bipolar disorder. The sample currently comprises more than 1,200 patients, characterized by their response to lithium treatment according to the Alda scale. Preliminary results from this international study suggest a possible involvement of the sodium bicarbonate transporter (SLC4A10) gene in lithium response. It is concluded that the pharmacogenetics of response to mood stabilizers has recently become a growing field of research, especially so far as the pharmacogenetics of the response to lithium is concerned. Clearly, the ConLiGen project is a highly significant step in this research. Although the results of pharmacogenetic studies are of significant scientific value, their possible practical implications are yet to be seen.
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Bipolar depression is as debilitating as mania in bipolar disorder, but the treatment of bipolar depression has historically received less attention. To date, there is no mood stabilizer (liberally defined as a medication that decreases episode severity, duration, or frequency in one phase of bipolar illness without producing a negative effect in other phases) that demonstrates similar efficacy in both the depressive and the manic phases of bipolar disorder. However, bipolar depression--which is prevalent, sometimes chronic, and associated with a low quality of life and a high risk of suicide--must be addressed as energetically as mania. Recent research into the long-term treatment of bipolar disorder has raised several questions about the generalizability of early lithium studies, as a result of these studies' designs. Researchers conducting more recent studies of mood stabilizers in the long-term treatment of bipolar disorder have attempted to clarify their results by, for example, performing survival analyses of the data. Until pharmacotherapy has been found that is equally efficacious in the treatment of both manic and depressive episodes in bipolar disorder, the use of combination therapy to manage bipolar disorder is advised. Lithium and divalproex sodium remain the first-line treatments for mania. Lamotrigine has been found to have acute efficacy in treating episodes of bipolar depression without increasing cycling or provoking a switch into mania, as well as a long-term role in delaying relapse and recurrence of depressive episodes.
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The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re‐examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood‐cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long‐term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15–20% of bipolar depressed patients).
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Sir: Schizotypal personality disorder (SPD) is characterized by odd, eccentric behavior; inappropriate or constricted affect; odd beliefs or magical thinking; circumstantial, metaphorical, or stereotyped thinking manifested by odd speech; anxiety in social situations; and cognitive or perceptual distortions. 1 Studies have been conducted on the efficacy of haloperidol, 2 thiothixene, 3 olanzapine, 4 and risperidone 5 in SPD.However, efficacy of aripiprazole in SPD has not been reported.Aripiprazole is a novel antipsychotic with a unique mechanism of action.It is a partial agonist of D 2 and D 3 dopamine receptors and 5-HT 1A serotonin receptors, which are, respectively, responsible for its efficacy on positive, negative, and cognitive symptoms of schizophrenia and its antidepressant and antianxiety actions. [6]7][8] Hence, it is called a dopamine-serotonin system stabilizer. 9,10Aripiprazole has been approved by the U.S. Food and Drug Administration in the treatment of schizophrenia.A search of English-language publications in PubMed using the keywords schizotypal personality disorder and aripiprazole retrieved no published reports or articles.Herein, we describe a patient with SPD of 5 years' illness duration who had never been treated with any medications and who responded to treatment with aripiprazole.Case report.Mr. A, a 22-year-old engineering student of middle-class socioeconomic status and urban background, presented to our hospital in August 2007 with an insidious onset and continuous course of illness of 5 years' duration characterized by odd and eccentric behavior, oddities in speech, avoidance of social situations, deteriorating academic performance, idiosyncratic repetitive behaviors, and magical thinking.His family members were concerned about his odd and eccentric behavior, social dysfunction, and academic decline.The above symptoms could not be attributed to any clear-cut psychotic disorders, mood disorders, substance use disorders, or general medical conditions.He had never received treatment for the symptoms.The patient's history and family history were noncontributory.Structured assessment conducted at baseline using the Structured Clinical Interview for DSM-IV Axis I Disorders 11 and Structured Clinical Interview for DSM-IV Axis II Personality Disorders 12 revealed that Mr. A had schizotypal personality disorder.The Schizotypal Personality Questionnaire (SPQ) 13 revealed social anxiety, odd beliefs, odd behaviors, blunted affect, suspiciousness, lack of close friends, and magical thinking.A baseline score of 4 on the Clinical Global Impressions-Severity of Illness scale (CGI-S) 14 was noted.Other baseline psychodiagnostic assessments were also conducted, such as the Object Sorting Test, Thematic Apperception Test, and Rorschach Inkblot Test, which revealed the absence of pathognomonic signs of psychosis.After giving informed consent, Mr. A was started on treatment with aripiprazole 10 mg at night.At 2-month (week 8) follow-up, the patient reported a 70% decrease in his symptoms, started attending his engineering college regularly, and showed interest in his studies.His family members reported marked improvement in his social and academic functioning.They also reported that his odd ideas, eccentric behaviors, magical thinking, and suspiciousness were reduced to minimal.His interaction with friends and his mood also improved.His CGI-S score was 3 (mildly ill), and his CGI-Improvement score was 2 (showing much improvement).This patient with SPD had a 5-year duration of untreated illness and was assessed with structured instruments.He responded to treatment with 10 mg of aripiprazole.Currently, thiothixene, haloperidol, risperidone, and olanzapine have been documented to be effective in treatment of SPD.This case report assumes importance in the light of the paucity of aripiprazole studies in SPD.However, the choice of antipsychotic medications is largely based on side effect profile.Available data on aripiprazole reveal that it is an effective medication with a benign adverse effect profile. 9,10Aripiprazole, being a dopamineserotonin system stabilizer, is hence an ideal drug to target the odd and eccentric behavior, stereotyped thinking, social anxiety symptoms, and obsessive symptoms of SPD.Future double-blind, placebo-controlled studies examining the effectiveness of aripiprazole in the treatment of SPD are needed.
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Bipolar II disorder is frequently misdiagnosed as major depressive disorder. In particular, correct diagnosis of bipolar II disorder may be delayed by years due to the predominance of depressive symptoms and the relative subtlety of hypomania, which may manifest only briefly and without elevated mood. The prevalence of bipolar II disorder varies from 0.5% to about 5% depending on the criteria used. Diagnosis can be improved by using mood disorder questionnaires, systematic probing, and prospective mood diary charting. There is a dearth of research into treatment of bipolar disorder. The limited available evidence suggests that lithium and lamotrigine may have efficacy in preventing relapse of mood episodes. Acute bipolar II depression could be treated with a combination of a mood stabilizer plus an antidepressant or pramipexole and in rare cases with antidepressant monotherapy. Hypomania will likely respond to monotherapy with antimanic agents. Adjunctive psychosocial treatments may provide additional benefit in patients with bipolar II disorder.
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