Evidence for Reduced Long-Term Potentiation-Like Visual Cortical Plasticity in Schizophrenia and Bipolar Disorder.

Several lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication. We measured the VEP of patients with SZ spectrum disorders (n = 31), BDI (n = 34), BDII (n = 33), and other BD spectrum disorders (n = 2), and age-matched healthy control (HC) participants (n = 200) before and after prolonged visual stimulation. Compared to HCs, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χ 2 = 35.1, P = 3.1 × 10-9) and BD spectrum (χ 2 = 7.0, P = 8.2 × 10-3), including BDI (χ 2 = 6.4, P = .012), but not BDII (χ 2 = 2.2, P = .14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χ 2 = 14.2, P = 1.7 × 10-4). N1b modulation was not significantly associated with Positive and Negative Syndrome Scale (PANSS) negative or positive symptoms scores, number of psychotic episodes, Montgomery and Åsberg Depression Rating Scale (MADRS) scores, or Young Mania Rating Scale (YMRS) scores after multiple comparison correction, although a nominal association was observed between N1b modulation and PANSS negative symptoms scores among SZ spectrum patients. These results suggest that LTP-like plasticity is impaired in SZ and BD. Adding to previous genetic, pharmacological, and electrophysiological evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.

The use of antidepressant medications for Bipolar I and II disorders.

Given that the patterns and clinical correlates related to antidepressant drugs (ADs) prescription for Bipolar Disorder (BD) remain generally unclear, this study aimed to compare socio-demographic and clinical features of BD patients treated vs. not treated with ADs. The sample consists of 287 currently euthymic bipolar patients. Among participants (mean age=51.9±15.02), 157 54.7% were receiving ADs. Based on the main findings, subjects given ADs were older and more frequently retired than those without receiving ADs. Moreover, patients given ADs were more likely to have had a first major depressive episode. Lifetime substance abuse/dependence history was less frequently reported among patients given ADs. Furthermore, ADs given patients had a higher number of affective episodes, and longer duration of their illness. Additionally, subjects treated with ADs reported higher hopelessness levels, and lower positive reinterpretations than those who were not treated with ADs. Factors associated with ADs-use by multivariate modeling were reduced personal autonomy (OR=.070), and hopelessness levels (OR=1.391). These results may help clinicians to better understand the clinical correlates of BD subtypes and improve their differential management. Additional studies are needed to replicate these findings, and facilitate the differential trajectories of BD patients based on socio-demographic/clinical profiles.

Lithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A 1H-MRS study.

OBJECTIVE: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (1H-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC. METHODS: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (1H-MRS) using a PRESS ACC single voxel (8cm3) sequence. RESULTS: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy). CONCLUSION: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics.

Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia. METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference. RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre. CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD.

Antidepressants and Mood Stabilizers: Novel Research Avenues and Clinical Insights for Bipolar Depression.

The concept of the bipolar-spectrum and of mixed features being a bridge between major depressive disorders and bipolar disorders (BDs) has become increasingly important in mood-disorder diagnoses. Under these circumstances, antidepressants (ADs) and mood stabilizers (MSs) should be used with caution in the treatment of major depressive episodes (MDEs) and to obtain long-term stability in BDs. Before treating MDEs, screening tools, specific symptom evaluation and medical history should be used to distinguish between bipolarity and mixed features in patients for whom AD monotherapy may present a risk. In these patients, a combination of ADs plus MSs or atypical antipsychotics is recommended, rather than AD monotherapy. Studies evaluating MSs for bipolar depression suggest that lamotrigine is the most reliable treatment and lithium has modest effects; there is a lack of clear evidence regarding the efficacy of valproate and carbamazepine. Recently, significant progress has been made with respect to the pathophysiology of mood disorders and the application of potential biomarkers. There is an opportunity to study novel drug mechanisms through the rediscovery of fast-acting drugs such as ketamine. It is anticipated that future research developments will involve the discovery of potential targets for new drugs and their application to personalized treatments.

Trait-related alterations of N-acetylaspartate in euthymic bipolar patients: A longitudinal proton magnetic resonance spectroscopy study.

BACKGROUND: Neurochemical changes are responsible for bipolar disorder (BD) pathophysiology. Despite current progress in BD research, mood- and trait-related alterations in BD continue to elicit further investigation. METHODS: In this study, we report a longitudinal proton magnetic resonance spectroscopy study evaluating dorsomedial prefrontal cortex (DMPFC) metabolites N-acetylaspartate (NAA), creatine plus phosphocreatine (total creatine [tCr]), phosphorylcholine plus glycerophosphocholine, myo-inositol, and glutamate plus glutamine levels of manic and euthymic adult BD type I patients (n=48) treated with standard antimanic medicines, compared to matching healthy controls (n=44). RESULTS: DMPFC NAA values and NAA/tCr ratio were significantly lower in euthymic BD patients when compared with healthy controls with similar levels of other metabolites in all groups, indicating a trait-related NAA abnormality in euthymic BD patients. LIMITATIONS: of our study include a relatively low (1.5T) magnetic resonance field strength and variable drugs administered to achieve euthymia despite the best efforts to standardize the open fashion treatment. CONCLUSIONS: Our study contributes to the integrating models of trait-related metabolite alterations observed in euthymia since NAA is considered as a marker of neuronal viability and mitochondrial energy metabolism. In light of supporting and conflicting results reported previously, future studies with longitudinal designs and larger patient groups are warranted to better define both state- and trait-related cerebral metabolic alterations associated with BD pathophysiology.

A Randomized Controlled Trial of Individual Family Psychoeducational Psychotherapy and Omega-3 Fatty Acids in Youth with Subsyndromal Bipolar Disorder.

OBJECTIVE: This pilot study evaluates efficacy of omega-3 fatty acid supplementation (Ω3), individual family psychoeducational psychotherapy (IF-PEP), and their combination in youth with subsyndromal bipolar disorders (bipolar disorder not otherwise specified [BP-NOS], cyclothymic disorder [CYC]). METHODS: This study was a 12 week, randomized trial of Ω3 versus placebo and IF-PEP versus active monitoring (AM) using a 2 × 2 design (Ω3 + PEP: n = 5; Ω3 + AM: n = 5; placebo + PEP: n = 7; placebo + AM: n = 6). Twenty-three youth ages 7-14 with BP-NOS or CYC were recruited via community advertisements and clinician referrals. Participants could be taking stable medication for attention-deficit/hyperactivity disorder and sleep aids, but no other psychotropics. Independent evaluators assessed participants at screen, baseline, and 2, 4, 6, 9, and 12 weeks. Primary outcome measures were the Kiddie Schedule for Affective Disorders (K-SADS) Depression (KDRS) and Mania (KMRS) Rating Scales, Children's Depression Rating Scale-Revised (CDRS-R), and Young Mania Rating Scale (YMRS). Ω3/placebo conditions were double-blind; independent evaluators were blind to psychotherapy condition. RESULTS: Most participants (83%) completed the 12 week trial. Side effects were uncommon and mild. Intent-to-treat analyses indicated significant improvement in depressive symptoms (KDRS) for combined treatment relative to placebo and AM (p = 0.01, d = 1.70). Across groups, manic symptoms improved over time without significant treatment effects. Effect of IF-PEP on child depression compared with AM was medium (d = 0.63, CDRS-R) to large (d = 1.24, KDRS). Effect of Ω3 on depression was medium (d = 0.48, KDRS). CONCLUSION: IF-PEP and Ω3 are well tolerated and associated with improved mood symptoms among youth with BP-NOS and CYC. Clinicaltrials.gov Identifier: NCT01507753.

BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis.

BACKGROUND: Peripheral brain-derived neurotrophic factor (BDNF) is decreased in acute major depressive disorder (MDD) and bipolar disorder (BD) and recovered after treatment. Here we validated on a meta-analytical level whether BDNF restores differentially according to treatment response and whose measurements could be used as a biomarker, plasma or serum. METHODS: Using strict inclusion criteria, we compared BDNF in healthy controls and patients with MDD (38 studies, n=6619), and BD (17 studies, n=1447). Pre- and post-treatment BDNF levels were meta-analyzed according to treatment response in patients from 21 MDD studies (n=735) and 7 BD studies (n=88). Serum and plasma subgroups were analyzed, publication bias was assessed and heterogeneity was investigated. RESULTS: Serum and plasma BDNF were decreased in acute MDD and BD, and did not differ in euthymia in comparison with control subjects. Antidepressive treatment increased serum BDNF levels in MDD in responders (Cohen׳s d (d)=1.27, p=4.4E-07) and remitters (d=0.89, p=0.01), significantly more than in non-responders (d=0.11, p=0.69). For plasma BDNF in MDD and for BD, the evidence was insufficient for a meta-analysis. Although no significant difference was found between serum and plasma ES, variance of plasma ES was higher. LIMITATIONS: Between-study heterogeneity was explained only partially; signs of publication bias in serum studies. CONCLUSION: Serum BDNF might be regarded as a biomarker for the successful treatment of MDD. Serum measurements seem more reliable than plasma ones. Further research should focus on defining optimal time points for BDNF measurements and increase evidence for the usage of BDNF as a predictive biomarker in BD.

Religious involvement in major depression: protective or risky behavior? The relevance of bipolar spectrum.

BACKGROUND: Religiosity has been reported to be inversely related to depression and to suicide as well, but there is a lack of studies on its impact on bipolar disorder and especially, on depressed patients belonging to the bipolar spectrum. METHODS: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 234 (55.2%) could be classified as with high religious involvement (HRI), and 190 (44.8%) as with low religious involvement (LRI), on the basis of their ratings on the Duke Religious Index (DRI). RESULTS: Compared to LRI, HRI patients did not differ with respect to their religious affiliation but had a later age at onset of their affective illness with more hospitalizations, suicide attempts, associated hypomanic features, switches under antidepressant treatment, prescription of tricyclics, comorbid obsessive compulsive disorder, and family history of affective disorder in first-degree relatives. The following independent variables were associated with religious involvement: age, depressive temperament, mixed polarity of first episode, and chronic depression. The clinical picture of depressive patients with HRI was evocative of chronic mixed depressive episodes described in bipolar III patients within the spectrum of bipolar disorders. LIMITATIONS: Retrospective design, recall bias, lack of sample homogeneity, no assessment of potential protective and risk factors, and not representative for all religious affiliations. CONCLUSIONS: In depressive patients belonging to the bipolar spectrum, high religious involvement associated with mixed features may increase the risk of suicidal behavior, despite the existence of religious affiliation.

Cyclothymia.

Over the last three decades, cyclothymia has been positioned in one of two principal ways: formally classified as a mood disorder, and less formally categorized at a "cyclothymic temperament" (CT) level. This review considers its historic evolution and provides five models for conceptualizing independence or interdependence between cyclothymia as a temperament style and as a formal mood disorder. Findings argue for CT to be conceded and appropriately defined. Secondly, it is recommended that cyclothymia's expression as a mood disorder should be positioned within the bipolar II disorder class-albeit perhaps having briefer mood swings and fewer episodes, more rapid cycling, and greater reactivity to environmental factors than is conceptualized currently for bipolar II disorders. By allowing cyclothymia both axis I and axis II status (although necessitating differing terminology), research evaluating any shared biological underpinnings and any predisposition provided by the CT temperament style to a later formalized bipolar II condition would be advanced.

Antidepressant-associated mania or hypomania: a comparison with personality and bipolarity features of bipolar I disorder.

BACKGROUND: Hypomania/mania during antidepressant treatment is often neglected by clinicians. There are no specific diagnostic criteria for hypomania and mania associated by antidepressant treatment in the bipolar spectrum. The aim of this study is to compare various characteristics of bipolar I disorder and antidepressant-associated mania. METHOD: In this study, 76 bipolar patients who met DSM-IV criteria for bipolar disorder-type I in remission from mania or depression (Group 1; n = 44) and patients with major depression in remission, who had mania associated by antidepressant treatment (Group 2; n = 32), were admitted. All patients were assessed using the SCID I, Bipolarity Index (BI) and a patient data form. First-degree relatives of all patients were evaluated using the Mood Disorder Questionnaire (MDQ). RESULTS: Sociodemographic features of both groups were similar. The rate of major depression in the relatives of Group 2 was significantly higher than in Group 1. The severity of manic symptoms in Group 2 was significantly lower than in Group 1. Those in Group 2 who were diagnosed with their first episode had atypical depressive features. First-degree relatives of patients in Group 1 had higher positive scores on the MDQ. A statistically significant difference was found between the two groups on all dimensions of the BI except family history. LIMITATIONS: This is a cross-sectional study with a relatively small number of subjects. There is no control group of major depressive patients who did not develop mania during antidepressive treatment. CONCLUSIONS: Our results suggest that antidepressant-associated hypomania/mania could be a different subgroup in the bipolar spectrum.

The precipitants of manic/hypomanic episodes in the context of bipolar disorder: a review.

BACKGROUND: Mania/hypomania is the hallmark feature of bipolar disorder. This paper aims to review the current evidence in relation to factors hypothesised to precipitate bipolar mania/hypomania, and suggest areas for future research. METHODS: A selective review of original and review papers was conducted. The electronic databases 'PsycINFO' and 'PubMed' were searched using the following search strings: "bipolar disorder" or "mania" or "hypomania" or "manic-depression" with "triggers" or "precipitants" or "precedents" or "predictors". RESULTS: There is evidence that goal attainment events, antidepressant medication, disrupted circadian rhythms, spring/summer seasonal conditions, and more tentatively, stressful life events and high emotional expression, may precipitate bipolar mania/hypomania in susceptible individuals. Evidence from case reports and clinical observations are also reported. DISCUSSION: The pathways to bipolar mania/hypomania may be many and varied, and many of these pathways may be outside the awareness of individuals with bipolar disorder. Greater awareness of the broad number of precipitating factors is needed to inform self-management and psycho-educational programs to build resilience to further episodes. Future research is needed to explore what other factors may precipitate bipolar mania/hypomania, and to determine why some factors may precipitate mania/hypomania in some individuals with bipolar I or II disorder but not in others.

Zonisamide for bipolar disorder, mania or mixed states: a randomized, double blind, placebo-controlled adjunctive trial.

OBJECTIVE: This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar mania or mixed state. EXPERIMENTAL DESIGN: One hundred four patients with Bipolar Disorder, Type I, II or NOS, in a manic, hypomanic or mixed state of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases: a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. The primary outcome variable for manic and hypomanic patients was the Young Mania Rating Scale (YMRS) both the YMRS and Montgomery Asberg Depression Rating Scale (MADRS) served as primary outcome variables for patients in mixed states. Secondary outcome measures included the Clinical Global Impression for Bipolar Disorder (CGI-BP), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also analyzed. Side effects were measured using the SAFTEE. PRINCIPAL OBSERVATIONS: There were no statistically significant differences for any of the primary or secondary outcome measures between zonisamide and placebo-treated patients. CONCLUSIONS: In contrast to previous studies that suggested efficacy of adjunctive zonisamide in bipolar mania or mixed state, these results were not confirmed in this double blind controlled study.

Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: a prospective, 18-month follow-up study.

OBJECTIVE: Most research on the symptomatic burden in bipolar disorder has included patients enrolled exclusively from tertiary centers, and only a few studies have analyzed factors related to it. We investigated the proportion of time and the proportion of visits with symptoms in a cohort of bipolar outpatients followed-up for 18 months, as well as the associated variables. METHODS: 296 DSM-IV-TR bipolar outpatients were included in a naturalistic longitudinal follow-up study, with quarterly assessment. Euthymia was defined by a Hamilton Depression Rating Scale score <7 and Young Mania Rating Scale score <5. Depressive episode, by a HDRS score of >17, hypomanic episode by a YMRS score of 10-20, and manic episode by a YMRS score >20. Sub-syndromal symptoms required scores of 7-17 in HDRS and 5-10 in YMRS. Based on a detailed recall of affective symptoms in the time between interviews, time in episode was also determined. RESULTS: Patients were symptomatic for one third of the follow-up, and also one third of the visits. They spent three times more days depressed than manic or hypomanic. More prior affective episodes were related both to more time symptomatic and more visits with symptoms. LIMITATIONS: Some of the data were collected retrospectively. Treatment was naturalistic. CONCLUSIONS: In a bipolar outpatient cohort from Spain, time with symptoms was shorter than previously found in tertiary care settings. In accordance with other longitudinal studies, those patients spent much more time depressed than manic.

Low-dose quetiapine for patients with dysregulation of hyperthymic and cyclothymic temperaments.

Patients with hyperthymic and cyclothymic temperaments often develop symptoms that fail to meet diagnostic criteria for bipolar disorders. These patients can be conceived as having bipolar disorder NOS (not otherwise specified), a bipolar spectrum disorder, cyclothymic disorder or cluster B personality traits. Here, we describe four of these patients with mild to moderate symptoms affecting mood, behaviour, emotional reactivity and sleep. Treatment with low-dose quetiapine (25-75 mg/day at night) lead to sustained symptom remission. Two of them were on quetiapine monotherapy. Such low doses occupy a minority of D2 and 5-HT2 receptors, which may nevertheless be of therapeutic value in mild cases. Alternatively, other mechanisms more likely to occur at low doses, such as antagonism of H1, alpha(1B)-adrenergic and other serotonin receptors, as well as reduction cortisol secretion, may be involved in the therapeutic efficacy of quetiapine.

Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD.

BACKGROUND: Many patients with bipolar disorder receive multi-drug treatment regimens, but the distinguishing profiles of patients who receive complex pharmacologies have not been established. METHOD: Prescribing patterns of lithium, anticonvulsants, antidepressants, and antipsychotics were examined for 4,035 subjects with bipolar disorder (DSM-IV) immediately prior to entering the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Subjects were recruited for participation across 22 centers in the United States between November 1999 and July 2005. The quality receiver operating characteristic (ROC) method was used to develop composite profiles of patients receiving complex regimens (p < .01 for all iterations). RESULTS: Use of 3 or more medications occurred in 40% of subjects, while 18% received 4 or more agents. Quality ROC analyses revealed that subjects had a 64% risk for receiving a complex regimen (> or = 4 medications) if they had (1) ever taken an atypical antipsychotic, (2) > or = 6 lifetime depressive episodes, (3) attempted suicide, and (4) an annual income > or = $75,000. Complex polypharmacy was least often associated with lithium, divalproex, or carbamazepine and most often associated with atypical antipsychotics or antidepressants. Contrary to expectations, a history of psychosis, age at onset, bipolar I versus II subtype, history of rapid cycling, prior hospitalizations, current illness state, and history of alcohol or substance use disorders did not significantly alter the risk profiles for receiving complex regimens. CONCLUSION: Complex polypharmacy involving at least 4 medications occurs in approximately 1 in 5 individuals with bipolar disorder. Use of traditional mood stabilizers is associated with fewer cotherapies. Complex regimens are especially common in patients with substantial depressive illness burden and suicidality, for whom simpler drug regimens may fail to produce acceptable levels of response. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00012558.

Hypericum and nurses: a comprehensive literature review on the efficacy of St. John's Wort in the treatment of depression.

PURPOSE: Many patients look to complementary and alternative medicine for a herbal solution to depression. This literature review summarizes recently published research on the treatment of depression using St. John's wort (Hypericum perforatum). CONCLUSIONS: The compounds in St. John's wort herbal preparations are more effective than placebo and, in several studies, more effective than common antidepressant medications in treating minor depression. However, the efficacy of St. John's wort for treating major depression, cyclothymia, or bipolar disorder is less evident. Although some studies are promising in the treatment of these major disorders, research support is lacking, and it is a controversial aspect of Hypericum therapy. PRACTICE IMPLICATIONS: As with any herbal treatment, risks from adverse reactions and drug interactions exist. Providers have an ethical and legal obligation to stay current in knowledge and to provide useful, accurate information to patients.

Rapid cycling bipolar disorder--diagnostic concepts.

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

Treatment adherence and illness insight in veterans with bipolar disorder.

Insight into the perceived value of psychotherapy and pharmacological treatment may improve adherence to medication regimens among patients with bipolar disorder, because patients are more likely to take medication they believe will make them better. We conducted a cross-sectional survey of patients recruited into the Continuous Improvement for Veterans in Care-Mood Disorders (CIVIC-MD; July 2004-July 2006), assessing therapeutic insight and 2 measures of medication adherence: the Morisky scale of intrapersonal barriers and missing any doses the previous 4 days. Among 435 patients with bipolar disorder, 27% had poor adherence based on missed dose and 46% had poor adherence based on the Morisky. In multivariable models, greater insight into medication was negatively associated with both measures of poor adherence. Odds of poor adherence increased for women, African Americans, mania, and hazardous drinking. The association of mutable factors-hazardous drinking, manic symptoms, and insight-could represent an opportunity to improve adherence.