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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 Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

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., (Copyright © 2020. Published by Elsevier B.V.)

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 ( 1 H-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 ( 1 H-MRS) using a PRESS ACC single voxel (8cm 3 ) 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy ( 1 H-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 1 H-MRS during euthymia., Methods: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1 H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm 3 ) 1 H-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 1 H-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., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest.

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., Competing Interests: The authors report no biomedical financial interests or potential conflicts of interest related to this study. BA was a researcher in Dokuz Eylul University at the time the study analysis and manuscript preparations were conducted and is now working as a full-time employee in Bristol-Myers Squibb. The research is not connected to the employment of BA with Bristol-Myers Squibb., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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., (© 2012 Wiley Periodicals, Inc.)

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (Copyright © 2010 Elsevier B.V. All rights reserved.)

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.

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., (2009 Elsevier B.V. All rights reserved.)

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.

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., (Copyright 2009 Physicians Postgraduate Press, Inc.)

Trichotillomania an impulse disorder that causes people to pull out the hair) is a relatively rare psychiatric illness, though the number of patients in need are definitely much higher than that we encounter in psychiatric practice. According to ICD-10 and DSM-IV-TR trichotillomania is an impulse disorder but latest researches in neurobiology and picture taking procedures seem to provide convincing evidence of it's being a relative of addictions. The article is a glimpse into the core of the newest literature also focusing on therapeutical solutions. The therapeutical effects of mode stabilizers as lamotrigine appear to gain on significance in the treatment of compulsive-impulsive illnesses such as trichotillomania. The article points out the especially high comorbidity with depression and dysthymia (OCD) and focuses on the psychopathologic impact of early traumas. In the case study many elements of the complex therapy of trichotillomania are also displayed.

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.

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.

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.

Purpose: A case of acute dystonia related to rivastigmine use is reported., Summary: A 61-year-old Caucasian woman who had suffered from bipolar II disorder with rapid cycling for over 30 years was admitted to an inpatient psychiatry unit. In addition to bipolar II disorder, the patient had been previously diagnosed with early-stage Alzheimer's disease, posttraumatic stress disorder, and various anxiety disorders. During the current hospitalization, she was taking clonazepam, dextroamphetamine, lamotrigine, lansoprazole, levothyroxine, memantine, quetiapine, risperidone, rivastigmine, tranylcypromine, trazodone, and zolpidem. Soon after hospital admission, she began to complain of a tightening in her chest. A review of her records revealed similar complaints during previous hospitalizations. Rivastigmine was discontinued due to concerns of interactions with her antipsychotic regimen. Although these symptoms were previously attributed to anxiety, they appeared worse during this hospitalization. During these events she would be witnessed lying in bed in a supine position with her head canted posteriorly. Benztropine was given to help determine if she was having a dystonic reaction. Within 30 minutes, her chest discomfort began to resolve, and her symptoms resolved completely over the next 48 hours. Three days later, rivastigmine was restarted by the attending psychiatrist because of concerns about the patient's memory, and the dystonia-like symptoms returned within 2 hours of her morning dose. Rivastigmine was discontinued, and benztropine was given and then discontinued, with no return of symptoms for the remainder of her two-week hospitalization., Conclusion: A patient with bipolar II disorder and mild-to-moderate Alzheimer's disease developed dystonia, possibly caused by rivastigmine. However, the patient was taking various other medications that could have lowered the threshold for extrapyramidal syndromes.

The importance of observing swings above euthymic normality in patients with affective disorders has been emphasized by many research groups. The concept of mood bipolarity has not only established a Bipolar II disorder (with only hypomania, not mania, but also opened up for discussion of a Bipolar Spectrum, that would necessitate treatment with a broader range of agents, i.e., not only antidepressants. In order to understand the determinants of the patterns of mood swings in individuals with bipolar disorder we have used a computerized life-charting technique to analyze a large amount of clinical information in 100 patients with bipolar mood swings. In a cross-sectional set-up, we demonstrate clear evidence of achieving a better long-term stabilization when starting patients on mood stabilizer early after the first evidence of the mood disorder.

Introduction: The psychopharmacology of aggression in youth is relatively unexplored, even though such maladaptive aggression manifests across many different diagnoses., Methods: This study was a 12-week, open-label trial with divalproex sodium (DVPX) in 24 bipolar offspring 6-18 years of age (mean age = 11.3 years; 17 boys) with mixed diagnoses of major depression, cyclothymia, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The Overt Aggression Scale (OAS) was used to measure aggression in 4-week intervals. We measured serum gamma-butyric acid (GABA) and glutamate levels at baseline and week 12., Results: Seventy-one percent of evaluable subjects were considered responders to DVPX treatment by the OAS. There was a significant correlation between the Young Mania Rating Scale (YMRS) and OAS scores at week 0 (p = 0.036) and week 12 (p = 0.025). Serum DVPX level did not correlate with treatment response., Conclusions: These youths who are at high risk for bipolar disorder experienced an overall decrease in aggressive behavior in response to DVPX. Age or gender did not predict a positive response to DVPX. This study is the first report of treatment efficacy of a mood stabilizer for aggression in youth at high risk for bipolar disorder.

Objectives: The Diagnostic and Statistical Manual of Mental Disorders guidelines provide only a partial solution to the nosology and treatment of bipolar disorder in that disorders with common symptoms and biological correlates may be categorized separately because of superficial differences related to behavior, life history, and temperament. The relationship is explored between extremely rapid switching forms of bipolar disorder, in which manic and depressive symptoms are either mixed or switch rapidly, and forms of borderline personality disorder in which affective lability is a prominent symptom., Methods: A MedLine search was conducted of articles that focused on rapid cycling in bipolar disorder, emphasizing recent publications (2001-2004)., Results: Studies examined here suggest a number of points of phenomenological and biological overlap between the affective lability criterion of borderline personality disorder and the extremely rapid cycling bipolar disorders. We propose a model for the development of 'borderline' behaviors on the basis of unstable mood states that sheds light on how the psychological and somatic interventions may be aimed at 'breaking the cycle' of borderline personality disorder development. A review of pharmacologic studies suggests that anticonvulsants may have similar stabilizing effects in both borderline personality disorder and rapid cycling bipolar disorder., Conclusions: The same mechanism may drive both the rapid mood switching in some forms of bipolar disorder and the affective instability of borderline personality disorder and may even be rooted in the same genetic etiology. While continued clinical investigation of the use of anticonvulsants in borderline personality disorder is needed, anticonvulsants may be useful in the treatment of this condition, combined with appropriate psychotherapy.

Rapid cycling (RC) bipolar disorder is defined as four or more affective episodes within one year. RC bipolar disorder constitutes one of the most difficult forms of the illness to treat effectively. According to several studies, RC bipolar patients have more severe symptoms than non-rapid cycling bipolar patients. Most studies indicate that only 10% to 20% of patients with bipolar disorders experience rapid cycling, but this is of great concern to psychiatrists because of its association with treatment refractoriness. Second generation antipsychotics are increasingly being used in the treatment of bipolar disorder. A first step in the management of rapid-cycling bipolar disorder is the thorough assessment of possible medications or environmental factors that may destabilize the disorder and contribute to the recurrence of episodes, increasing cycle frequency, or both. All currently approved antidepressant drugs pose some risk of mood destabilization, but the risk is highest for tricyclic antidepressants. Discontinuation of antidepressants should be the first step in the management of RC patients.

Background: The treatment of bipolar depression remains problematic. Lamotrigine has been shown in randomized controlled studies to be efficacious in preventing bipolar depression and rapid cycling states., Methods: Twenty-four women with cyclothymic temperament and refractory depression were recruited from four outpatient sites (three primary care and one psychiatric) and treated with lamotrigine in a naturalistic, open-label study. Temperament was determined by responses on the TEMP-A self-rating scale. Eighteen (75%) of these cyclothymic patients also scored high on the depressive temperament. Eighteen (75%) met DSM-IV criteria for bipolar II disorder. In two thirds of the cases, lamotrigine was add-on therapy to an antidepressant. Response to therapy was assessed using the DSM-IV Global Assessment of Functioning (GAF)., Limitations: This study was naturalistic in design, without controls or blinds., Results: Of the 23 patients who remained in the study, 16 (70%) had significant, sustained responses. Of these 16, 12 (75% of responders, 52% of the total) had remissions (GAF > 80) sustained longer than 12 months. Robust, sustained responses to lamotrigine monotherapy were seen in 4 patients (17%). Seven patients (30%) received no apparent benefit from lamotrigine., Conclusions: Lamotrigine induced prolonged illness remissions in a substantial number of female patients whose symptoms were both complex and refractory. Most manifested high scores on the cyclothymic and depressive temperaments, and prior refractoriness to multiple antidepressant and antidepressant/mood stabilizer combinations, before remitting with lamotrigine augmentation or monotherapy.

Relatively absent from previous studies of the pharmacotherapy for bipolar disorder is examination of the impact of comorbidity on treatment choices. This has occurred despite the presence of high levels of comorbid anxiety and substance use disorders, and the association of these disorders with severity and course markers of bipolar disorder. In this study, we examined comorbid disorders, identified by structured interviews, and the pharmacotherapy reported at study entry by the first 1000 patients entered into a large, multicenter study of bipolar disorder (Systematic Treatment Enhancement Program for Bipolar Disorder). Our study focused on the degree to which comorbid conditions are linked to the reported use of mood stabilizers deemed "minimally adequate" and the association between specific comorbidities and pharmacotherapy treatment, such as the use of anxiolytics in patients with anxiety disorders. Despite the presence of high levels of comorbidity, the presence of these disorders was only minimally associated with pharmacotherapy. Of the sample of bipolar outpatients, only 59% reported pharmacotherapy use meeting criteria for "minimally adequate" mood stabilizer, regardless of comorbid diagnoses, rapid cycling, or bipolar I or II status. Moreover, the cross-sectional use of "comorbidity-specific" pharmacotherapy for anxiety disorders, substance use disorders, and attention deficit disorder in this outpatient sample of patients with bipolar disorders was limited, suggesting that comorbid conditions in patients with bipolar disorder may be undertreated. Our findings highlight the need for greater clinical guidance and treatment options for patients with bipolar disorder and comorbidity.

The present study investigated possible clinical differences between bipolar patients with and without manic or hypomanic switch during antidepressant (AD) treatment. The authors undertook a retrospective assessment of 169 individuals affected by bipolar disorder type I (BP I: n=96) and II (BP II: n=73) who experienced at least one manic or hypomanic episode following depression without any interposed normothymic period ("manic switch") during AD therapy. They were compared with a sex, age (+/-5 years), and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects who have never had manic switches. Only 2 of the 169 patients had had spontaneous switches before the AD-related one. Switched subjects were marginally older (t=-2.65, df=414, P=.008) compared to not switched and less frequently delusional (chi2=13.86, P=.0002). Polarity of the onset episode was more frequently depressive in switched patients (chi2=21.93, P=.00002), which had also less previous manic episodes than not switched (t=3.44, df=332, P=.0006). Those differences were more pronounced in the BP I subsample. Switched patients were more frequently BP I (chi2=29.66; P<.00001). Maintenance with mood stabilizers appears to be a strong protective factor; in fact, of the 124 individuals undertaking a mood stabilizer therapy, 21 had a switch and 103 had no switches (chi2=41.10, P<.000001). In conclusion, some clinical variables, such as the number of manic episodes, the presence of delusions, the polarity of onset episode, and the mood-stabilizing treatment, may be involved in AD-related switches. Further studies are required to investigate the causal relationships between those factors.

Background: Lithium has been found to be effective in reducing suicide rates during long term treatment of patients with bipolar disorders. Data on the efficacy of anticonvulsant mood stabilizers in reducing suicide risk are sparse., Method: Charts of 140 bipolar patients treated continuously for a minimum of 6 months during a 23-year period of private practice by the senior author were extracted from nearly 4000 patient records. Data extracted from the charts were incidence of completed suicide, number of suicide attempts, and number of hospitalizations for suicidal ideation or behavior per 100 patient-years of either 'on' or 'off' lithium or anticonvulsant mood stabilizer monotherapy., Results: Only one completed suicide (during a period off of lithium) occurred in the patients studied. Incidence of non-lethal suicidal behavior was not different during treatment with lithium, compared with anticonvulsants. Being on a mood stabilizer significantly protected against suicidal behavior. The relative protective effect was more modest than in reports from other treatment settings., Limitations: This was a retrospective chart review study of naturalistically treated patients., Conclusions: Treatment of patients with bipolar disorder with either lithium or anticonvulsant mood stabilizers was associated with reduced risk of suicidal behavior. This study did not find evidence for a difference in the protective effect of the two types of mood stabilizing medications against non-lethal suicidal behavior in the naturalistic setting of private practice.

Recent evidence suggests that lithium therapy (even as supplemented by antidepressants and neuroleptics) is inadequate for the majority of patients with bipolar illness, and particularly those with rapid cycling. Valproate and carbamazepine have emerged as adjuncts and alternatives, but they, too, often require additional approaches with lithium, thyroid hormones, and other putative mood stabilizers, including nimodipine (and related dihydropyridine calcium channel blockers), lamotrigine, gabapentin, topiramate, and the atypical neuroleptics. Evaluating how these agents and the unimodal antidepressants are optimally applied and sequenced in the treatment of bipolar illness with its multiple subtypes, patterns and comorbidities will require much future investigation and the development of new methodological clinical trial approaches.

In 320 patients with established bipolar I disorder, we examined the past course on the basis of polarity at onset (depressive, mixed, and manic). Despite the obvious limitations of retrospective methodology, information on course parameters in a large sample of affective disorders is most practically obtained by such methodology. We believe that our systematic interview of patients and their relatives--as well as the systematic study of their records--minimized potential biases. Depressive onsets were the most common, accounting for 50%, followed by mixed and manic onsets in about equal proportion. In general, the polarity of episodes over time reflected polarity at onset. Those with depressive onset had significantly higher levels of rapid cycling, as well as suicide attempts, but were significantly less likely to develop psychotic symptoms. Mixed onsets, too, had high rates of suicide attempts, but differed from depressive onsets in having significantly more chronicity yet negligible rates of rapid cycling at follow-up evaluation. Because cases with depressive onset had received significantly higher rates of psychopharmacologic treatment, our data are compatible with the hypothesis that antidepressants may play a role in the induction of rapid cycling. Overall, our data support the existence of distinct longitudinal patterns within bipolar I disorder, which in turn appear correlated with the polarity at onset. In particular, rapid cycling and mixed states emerge as distinct psychopathologic processes.

Rapid cycling is a clinical subtype of bipolar mood disorder that has four or more episodes during the previous 12 months and has poor response to lithium (Li) prophylaxis treatment. Therefore it is said the refractory mood disorder and algorithm for treatment of rapid cycling is to be expected. The first choice of drug for rapid cycling is Li, the second choice is carbamazepine (CBZ) or valproic acid (VPA), in addition to Li, the third choice is clonazepam (CNZP) in addition to Li, and CBZ or VPA, the fourth choice is levothyroxine or bromocriptine in addition to them, and the fifth choice is electroconvulsive therapy.

This article argues for the necessity of a partial return to Kraepelin's broad concept of manic-depressive illness, and proposes definitions--and provides prototypical cases--to illustrate the rich clinical phenomenology of bipolar subtypes I through IV. Although considerable evidence supports such extensions of bipolarity encroaching upon the territory of major depressive disorder, further research is needed in this area. From a practice standpoint, the compelling reason for broadening the bipolar spectrum lies in the utility of mood stabilizers as augmentation or monotherapy in the treatment of major depressive disorders with soft bipolar features falling short of the current strict standards for the diagnosis of bipolar II and hypomania in DSM-IV and ICD-10.

The introduction of lithium salts almost a century ago and the subsequent approval of lithium carbonate for the treatment of patients with bipolar disorder represent one of the cornerstones of modern psychopharmacology. The onset of bipolar disorder in women often occurs during the childbearing years, which complicates the treatment decisions secondary to the possibility of conception while taking medication. The establishment of the lithium registry for fetal teratogenesis in the late 1960s ushered in a heightened level of concern for the use of lithium during the reproductive years; although, in the years to come, it has become apparent that alternative pharmacologic treatments for bipolar disorder may exceed the teratogenic risk of lithium monotherapy. In this paper, the available data on the use of antimanic medications during pregnancy and lactation are reviewed with an emphasis on providing a realistic risk/benefit assessment for medication selection and management of these patients. Treatment strategies are discussed for (1) women who are contemplating pregnancy (2) women who inadvertently conceive while taking medications (3) women who choose to become pregnant while taking medication, and (4) women who intend to breastfeed while taking medications.

This paper reviews recent evidence on two prevalent course patterns of major depressive illness arising from dysthymic and cyclothymic temperamental substrates. The first pattern, known as "double depression," typically begins insidiously in childhood or adolescence, pursues a low-grade intermittent course, and is complicated by superimposed highly recurrent major depressions. Patients with this pattern respond to TCAs, MAOIs (classical and reversible), and SSRIs (of which the best current evidence is for fluoxetine). The second pattern, that of "cyclothymic depression," is represented by bipolar II and related soft bipolar disorders; it pursues a more fluctuating course from onset in juvenile or early adult years, and appears susceptible to rapid cycling upon tricyclic antidepressant administration. For patients exhibiting the latter pattern, bupropion, MAOIs, and low-dose SSRIs all seem beneficial, but should be preferably used in conjunction with lithium or other mood stabilizers such as valproate; thyroid augmentation is particularly relevant to these cyclothymic depressions. Practical and supportive psychotherapeutic approaches would be useful for double depressive patients, while psychoeducation and attention to rhythmopathy would be more relevant for those with cyclothymic depressions. Conjugal and other interpersonal strains should also be addressed in both affective subtypes. The evidence reviewed does not support the commonly held belief that depressions associated with "personality" disorders respond suboptimally to treatment. On the contrary,the temperamental dysregulation underlying depressive subtypes defined by course appears responsive--even overresponsive--to a new spectrum of thymoleptic agents. These considerations underscore the close link between innovative temperament-based classifications of depressive illness and emerging clinical management strategies with thymoleptic agents and psychosocial interventions.

CNS-involvement in Coxiella burnetii infection is rare. Severe cerebellar symptoms with incomplete restitution were observed in 3 patients who developed Q-fever pneumonia associated with a long-term prophylaxis with lithium for manic-depressive disorder. Several pathophysiological mechanisms for these complications are discussed and a specific toxic-infectious interaction is suggested.

Background: Cyclothymic or hyperthymic temperaments may belong to a bipolar spectrum of disorders. Patients with such temperaments, especially if there is a family history of bipolar disorder or an exacerbation of these conditions when exposed to tricyclic antidepressants, should be conceptualized as possessing variants of bipolar disorder. This conceptualization suggests that standard psychopharmacologic regimens used in treating bipolar disorder may be useful. In this report I examine the potential usefulness of valproate in treating temperamental variants of bipolar disorder., Method: The author reports his experience of treating patients with bipolar temperamental disorders in an Outpatient Affective Disorder Specialty Clinic. Three representative case reports are offered, as well as a discussion of the general issues in the diagnosis and treatment of these patients., Results: In these cases, valproate not only treated the acute symptomatology that caused these patients to seek treatment, but also led to an amelioration of noxious life-long temperamental traits. These findings strengthen other research findings that suggest a link between bipolar disorder and limbic dysfunction and add to the validation of the concept of bipolar temperamental disorders., Conclusion: Valproate may be a safe and effective treatment for patients with cyclothymic and hyperthymic temperaments.

Background: Valproate has proved useful in the treatment of manic-depressive and schizoaffective disorders, usually in daily doses above 500 mg with corresponding blood levels in the range established for treatment of epilepsy (50-100 micrograms/mL). Since milder bipolar disorders may be more prevalent than bipolar I disorder, a prospective study was undertaken to determine whether lower doses of valproate might be useful for stabilization of mood cycling in patients having primary diagnoses of cyclothymia or rapid cycling bipolar II disorder. Additionally, open trials of low-dose valproate were conducted in a small number of women complaining of premenstrual syndrome., Method: Over a 3-year period, outpatients with non-menstrually-related rapid cycling who had fulfilled DSM-III-R criteria for cyclothymia or bipolar II disorder were started on open trials of valproate at daily doses of 125 or 250 mg. Doses were adjusted upward on approximately a monthly basis depending upon clinical response, and valproate blood levels were obtained., Results: Twenty-six (79%) of 33 patients (15 cyclothymics, 11 bipolar II) reported sustained partial or complete stabilization of mood cycling with valproate doses ranging from 125 to 500 mg (mean = 351.0 mg) corresponding to serum valproate levels (mean = 32.5 micrograms/mL) substantially below the current recommended range. Cyclothymics required significantly lower doses and blood levels of valproate than patients with bipolar II disorder for stabilization of mood. Five patients (all bipolar II) failed to respond fully to low doses of valproate but improved with higher doses corresponding to blood levels in the 50 to 100 micrograms/mL range. Two patients had poor responses to valproate or intolerable side effects. In contrast to bipolar spectrum patients, only three (38%) of eight women with menstrually related cycling of mood reported good responses to low doses of valproate, while five reported no response to valproate., Conclusion: The findings suggest that (1) low-dose valproate may be useful in the treatment of cyclothymia and milder rapid cycling bipolar disorders and (2) there may be a correlation between the severity of bipolar disorder and the blood level of valproate required for stabilization such that milder forms of bipolar cycling require lower doses of valproate.

81 remitted patients with bipolar affective disorder were examined 20 months after the last discharge from hospital, for personality disorders and other personality deviations, which could be important for their way of coping. There was a high frequency of narcissistic, histrionic and borderline traits and, especially in the bipolar schizoaffective subgroup, of schizoid and related traits. Patients with few former episodes seemed to be "syntonic". Bipolar patients with a longer duration of illness showed an increasing resignative and subdepressive change of feelings and attitudes, whereas the schizoaffective patients in the long term showed a hypomanic alteration. The personality changes of bipolar patients occur during the "free intervals" and are mediated by social interaction, whereas the alteration of some bipolar schizo-affective seems to be caused directly by their illness.

This paper describes five prototypes of depression which develop from different temperamental substrates: timid-inhibited, dysthymic, hyperthymic, cyclothymic and irritable. They correspond, respectively, to anxious depressions, double depressions, anergic depressions, rapid-cycling depressions, and hostile depressions. The author argues that, despite a certain degree of overlap in pharmacologic response, each prototype has a relatively unique profile, including benzodiazepines, MAOIs, SSRIs, TCAs, lithium, low dose neuroleptics and anti-epileptic agents.

The authors report 5 patients with bipolar disorders in the context of primary idiopathic dystonia. Four patients had DSM-III-R bipolar disorder, mixed, and one had cyclothymic disorder as diagnosed using the Structured Clinical Interview for DSM-III-R (SCID). All cases of bipolar disorder manifested rapid cycling. Three patients with bipolar disorder experienced onset of this illness soon after the onset of cervicocranial dystonia (5 neck dystonia, 4 craniofacial, 2 brachial, 1 vocal cord, 1 thoracic). These cases apparently represent a first report of bipolar disorders in dystonia. Clinical management, relevant literature, and putative neurobiology are reviewed.

We hereby report a case of manic depressive psychosis. The patient had been treated for years with lithium carbonate (600 mg/die, lithium serum concentration equal to 0.7 mEq/l) and came to us under observation for a sensorimotor peripheral neuropathy with mostly axonal degeneration. The central nervous system had not been involved. Excluding any possible causes of peripheral neuropathy and since no precipitating circumstances were ascertained, a clinical improvement was noticed after suspending the therapy.

We conducted an open clinical trial of desipramine hydrochloride or lithium carbonate as adjuncts to psychotherapy in cocaine abusers. Subjects who were treated with desipramine hydrochloride showed marked decreases in a measure of cocaine craving after two to three weeks of treatment and became abstinent regardless of whether an affective disorder was also present. Lithium carbonate was effective only in cyclothymic subjects. Other subjects treated with lithium carbonate, as well as nonpharmacologically treated subjects, continued their cocaine use.

The prophylactic effect of lithium was studied prospectively in 63 patients with recurrent affective disorders. Lithium treatment was started at recovery from a current episode of illness when the patients were able to participate in the decision to start long-term treatment. The median treatment time was 23.7 months and the mean serum lithium concentration approx. 0.63 mmol/l. Comparison with equally long control periods before lithium showed that the treatment resulted in statistically significant reductions in number of episodes, number of months ill, and number of months hospitalized. There were 40 (63%) responders (frequency of episodes during lithium lower than before lithium) and 23 (37%) non-responders (frequency of episodes during lithium higher than or the same as before lithium). Females responded slightly better than males. Responders scored significantly higher than non-responders in the psychasthenia and muscle tension subscales of the Karolinska Hospital Personality Inventory. Both responders and non-responders showed falls in CPRS during lithium treatment, the fall was statistically significant in the responders. During the first 4 months of lithium treatment the responders showed a significant rise in serum calcium, while serum calcium remained unaltered in the non-responders. These variables may be predictive of response to long-term lithium treatment. The low numbers of patients who discontinued treatment and the even serum levels of lithium suggest that good compliance to treatment was achieved with the present approach.

Of 27 cases, 18 manic-depressive patients who simultaneously fitted dunners' seminal definition about rapid cycling affective disorders (RCAD) completed clinical follow-up for 1.5-4.5 years after discharge between Jan, 1983 and Jun, 1986. The results showed that 8 cases relapsed into manic-depressive episodes, the other 10 cases had no relapsed. Only one case belonged to relapsing of RCAD during the follow-up duration. The cases with relapsing of depression responded to lithium or to stopping use of antidepressants, but the cases with relapsing of manic episodes responded to carbamazepine. The differences in therapeutic response in such cases suggested that RCAD probably presented biological heterogenecity.