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Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1).

Regional cerebral blood flow was studied in 17 bipolar I depressed patients (DSM-IV criteria) with single photon emission computed tomography (SPECT). Visual analysis of images revealed no abnormality in eight patients and abnormal findings in nine patients. In the nine patients with abnormal findings, all showed regional decreases of the uptake of (99m)Tc-D,L-hexamethylpropylene amine oxime (HMPAO, four in the frontal region, two in the basal ganglia, and three in both the frontal region and the basal ganglia). The patients with visible SPECT abnormalities had significantly higher scores on the Hamilton Rating Scale for Depression (HDRS).

Olanzapine is an effective drug for the long-term treatment of bipolar disorder but is associated with burdensome weight gain. Topiramate is a novel anticonvulsant that may induce weight loss in some patients. This is the first study to address the long-term efficacy and impact on weight of the combination of olanzapine and topiramate in bipolar patients. Twenty-six Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition bipolar spectrum patients received olanzapine plus topiramate cotherapy for treatment of their manic (n = 14), hypomanic (n = 6), depressive (n = 2), and mixed (n = 1) symptoms for 1 year. Three rapid cycling patients were also enrolled despite being euthymic. Efficacy was assessed with the Young Mania Rating Scale, the Hamilton Depression Rating Scale, and the Modified Clinical Global Impressions for Bipolar Disorder. Weight, body mass index, and side effects were collected at every visit. Thirteen (50%) patients completed the 1-year follow-up. By intent-to-treat, patients significantly improved from baseline in Young Mania Rating Scale scores (P < 0.0001), Hamilton Depression Rating Scale (P < 0.05), and Modified Clinical Global Impressions for Bipolar Disorder subscales (mania P < 0.0001, depression P < 0.05, overall P < 0.0001). Most patients gained weight during the first month of combined treatment (mean weight gain 0.7 +/- 0.6 kg), but at the 12-month endpoint, the mean weight change was -0.5 +/- 1.1 kg. The combination of olanzapine and topiramate was efficacious for the long-term treatment of bipolar patients and appeared to carry some benefits for controlling weight gain. Given the limitations of the open, uncontrolled design, further trials are warranted with this combination.

We evaluated the efficacy and safety of adjunctive topiramate in bipolar II patients who were either treatment-resistant to or unable to tolerate lithium, carbamazepine or valproate. Nineteen DSM-IV bipolar II patients received increasing doses of open-label topiramate as adjunctive therapy for their hypomanic (n=15) or depressive (n=4) symptoms. Sixteen patients completed the 12-week follow-up. There were highly significant improvements in YMRS, HDRS and CGI-BP-M scores (p=0.0001). Of the fifteen hypomanic patients, eight (53%) were rated as responders to topiramate (50% reduction in YMRS scores), and five (33%) met criteria for remission (YMRS score pound 8). Two of the four patients with a depressive episode at study entry (50%) were rated as responders (50% reduction in HDRS score), and one (25%) achieved remission (HDRS score pound 6). Topiramate was generally well tolerated. One third of the patients experienced weight loss. These preliminary results suggest that adjunctive topiramate may be useful in treating bipolar II disorder.

Methods: Fourteen rapid cycling bipolar patients were treated with quetiapine, which was added to their ongoing medication regimen for 112 ± 33 days. At the beginning of the study, five were manic, three were in a mixed state, three were depressed, two hypomanic and one was euthymic. Patients were assessed prospectively with a modified version of the Clinical Global Impression Scale for Bipolars (CGI-BP), the Young Scale for mania (YMRS)and the Hamilton Scale for Depression (HDRS). Results: A significant reduction of the following scale scores was observed: • a 1.8 point reduction for the general CGI-BP (p ¼ 0.013), • a –1.3 point for the mania subscale (p ¼ 0.016), • a –1.01 point for the YMRS (p ¼ 0.025). Improvement in depressive symptoms was not significant, neither in the CGI-BP (–1 point, p ¼ 0.074)nor in the HDRS (–5.2 points, p ¼ NS). The most common side-effect was sedation (n ¼ 6, 43%). Doses of quetiapine were significantly reduced by the end of the study (443 ± 235 mg/day versus 268 ± 190 mg/day, p ¼ 0.008)and they also differed according to the initial episode to be treated (720 ± 84 mg/day for mania, and 183 ± 29 mg/day for depression, p ¼ 0.023). Conclusions: Quetiapine could possibly be an effective treatment for rapid cycling bipolar patients. Adequate doses for acute episodes could significantly differ according to the episode polarity and the length of treatment.

To make clinically relevant recommendations for chest X-ray testing in acute psychiatric admissions, this study examined the current practice of this screening test in patients admitted to a University Hospital. The records of the 332 first consecutive admissions to the psychiatric ward were assessed. In 200 patients (60%) a chest X-ray was requested. The X-ray film was normal in 81.5% of patients. The remaining subjects presented abnormalities: nonrelevant in twenty-seven (13.5% of the total), and relevant in eleven (5.5%). Since all these relevant abnormalities were already known, in no cases was the test followed by changes in therapy or by additional diagnostic procedures. In almost all cases this screening test was of no practical value. Our findings challenge the systematic indication of chest X-ray in acute psychiatric patients, and suggest that the number of tests performed and the cost of medical care could be reduced by a more efficient use of past medical history and physical examination criteria, without compromising the quality of patient care.

OBJECTIVES To ascertain the clinical implications of psychiatric comorbidity in the course and outcome of bipolar I patients. METHODS One hundred and twenty-nine bipolar I outpatients in remission [Young Mania Rating Scale (Y-MRS) < 7, Hamilton Depression Rating Scale (HDRS) < 9] were assessed by means of the Structured Clinical Interview for DSM-III-R axis I and axis II (SCID-I and SCID-II) in order to detect all possible psychiatric comorbid diagnoses. The sample was split according to the presence of psychiatric comorbidity and the groups were compared. RESULTS Psychiatric comorbidity was detected in 31% of the sample. A higher number of mixed features, depressive episodes and suicide attempts and a predominance of depressive onset amongst comorbid bipolar patients were the most relevant differences between the two groups. CONCLUSIONS There is an association between depression, suicidality and comorbidity in bipolar I disorder. As comorbidity had a clear relevance in the course and outcome of bipolar illness, this issue should be specifically assessed in clinical practice.

Studies on individual psychotherapy indicate that some interventions may reduce the number of recurrences in bipolar patients. However, there has been a lack of structured, well-designed, blinded, controlled studies demonstrating the efficacy of group psychoeducation to prevent recurrences in patients with bipolar I and II disorder.One hundred twenty bipolar I and II outpatients in remission (Young Mania Rating Scale score6, Hamilton Depression Rating Scale-17 score8) for at least 6 months prior to inclusion in the study, who were receiving standard pharmacologic treatment, were included in a controlled trial. Subjects were matched for age and sex and randomized to receive, in addition to standard psychiatric care, 21 sessions of group psychoeducation or 21 sessions of nonstructured group meetings. Subjects were assessed monthly during the 21-week treatment period and throughout the 2-year follow-up.Group psychoeducation significantly reduced the number of relapsed patients and the number of recurrences per patient, and increased the time to depressive, manic, hypomanic, and mixed recurrences. The number and length of hospitalizations per patient were also lower in patients who received psychoeducation.Group psychoeducation is an efficacious intervention to prevent recurrence in pharmacologically treated patients with bipolar I and II disorder.

This prospective open-label study assessed the impact of add-on quetiapine in the treatment of rapid cycling bipolar patients.Fourteen rapid cycling bipolar patients were treated with quetiapine, which was added to their ongoing medication regimen for 112 +/- 33 days. At the beginning of the study, five were manic, three were in a mixed state, three were depressed, two hypomanic and one was euthymic. Patients were assessed prospectively with a modified version of the Clinical Global Impression Scale for Bipolars (CGI-BP), the Young Scale for mania (YMRS) and the Hamilton Scale for Depression (HDRS).A significant reduction of the following scale scores was observed: a 1.8 point reduction for the general CGI-BP (p = 0.013), a -1.3 point for the mania subscale (p = 0.016), a -1.01 point for the YMRS (p = 0.025). Improvement in depressive symptoms was not significant, neither in the CGI-BP (-1 point, p = 0.074) nor in the HDRS (-5.2 points, p = NS). The most common side-effect was sedation (n = 6, 43%). Doses of quetiapine were significantly reduced by the end of the study (443 +/- 235 mg/day versus 268 +/- 190 mg/day, p = 0.008) and they also differed according to the initial episode to be treated (720 +/- 84 mg/day for mania, and 183 +/- 29 mg/day for depression, p = 0.023).Quetiapine could possibly be an effective treatment for rapid cycling bipolar patients. Adequate doses for acute episodes could significantly differ according to the episode polarity and the length of treatment.

The aim of this study was to estimate the long-term effectiveness of olanzapine as adjunctive therapy in patients with bipolar disorder who exhibited an inadequate response to mood stabilizers. Twenty-three Research Diagnostic Criteria (RDC) patients with bipolar I and II were assessed by means of the Schedule for Affective Disorders and Schizophrenia and entered if they gave their consent to participate. All of them had experienced frequent relapses, residual subsyndromal symptoms, and inadequate responses to other drugs, such as lithium, valproate, or carbamazepine. While maintaining other drugs, they all received open-label, increasing doses of olanzapine, until achieving clinical response. Other drugs were maintained. The patients were assessed several consecutive times from baseline to the endpoint with the Clinical Global Impressions (CGI) scale for use in bipolar illness. Records of recurrences, hospitalizations, and side effects were also collected. The last-observation-carried-forward analysis showed that there was a significant reduction of CGI scores after the introduction of olanzapine, either in manic symptoms (p = 0.0015), depressive symptoms (p = 0.0063), or global symptoms (p = 0.0003). The most frequent adverse events were somnolence (17%) and weight gain (13%). The mean dose of olanzapine at the end of the 43-week follow-up was 8.1 mg/day. Olanzapine may be a useful medication for the long-term adjunctive treatment of patients with bipolar disorder who exhibit a poor response to mood stabilizers, such as lithium, valproate, or carbamazepine. These results suggest mood-stablizing properties of olanzapine.

Background: The goal of this study was to assess the efficacy and safety of risperidone in bipolar and schizoaffective disorders. Method: 541 patients entered this open, multicenter, 6-month study. Patients were entered provided that they fulfilled DSM-IV criteria for bipolar disorder or schizoaffective disorder, bipolar type, during a manic, hypomanic, mixed, or depressive episode. Risperidone was added to any previous mood-stabilizing medication that the patients were taking. Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions scale (CGI). Extrapyramidal symptoms (EPS) were assessed using the UKU Side Effect Rating Scale. Results: 430 patients completed the study. Addition of risperidone produced highly significant improvements (p