Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses.

BACKGROUND: Neurons in the basal ganglia are connected to areas of prefrontal cerebral cortex involved in higher cognitive functions, and these connections occur primarily via the thalamus. In patients with bipolar disorder, regardless of age, neuroimaging studies have consistently reported an increased number of white matter hyperintensities, indicating possible alterations in striatum-thalamus and thalamus-prefrontal cortex connections. METHODS: In the current study, we acquired high-resolution magnetic resonance imaging (MRI) and diffusion tensor (DT) scans of 40 patients with bipolar spectrum (BPS) illnesses (bipolar type I = 17, bipolar type II = 7, cyclothymia = 16) and 36 sex- and age-matched control subjects. Two researchers, without knowledge of diagnosis, outlined the caudate, putamen, and thalamus on contiguous axial MRI slices. We measured the volumes of the basal ganglia, thalamus, and gray/white matter of the frontal cortex. RESULTS: Bipolar spectrum patients as a single group did not differ from control subjects in thalamus and the basal ganglia volumes, but the cyclothymia patients had reductions in the volumes of putamen and the thalamus compared with control subjects. The BPS patients had significantly reduced volume of the white and the gray matter of the frontal cortex. Furthermore, compared with control subjects, BPS patients as a group showed alterations in anisotropy of the internal capsule adjacent to the striatum and thalamus and the frontal white matter. CONCLUSIONS: Our findings indicate that BPS patients may have distinct anatomical alterations in brain structures involved in the regulation of mood and cognition, as well as alterations in these structures' connection to related brain areas.

Does sustained-release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders?

OBJECTIVE: Selective serotonin reuptake inhibitors may be effective for some patients with pathological gambling, but those with comorbid conditions, such as bipolar spectrum disorders, may relapse during treatment. To the authors' knowledge, this is the first placebo-controlled treatment study in pathological gamblers with bipolar spectrum disorders; it compares sustained-release lithium carbonate to placebo. METHOD: Forty pathological gambling patients with bipolar spectrum disorders entered a 10-week randomized, double-blind, placebo-controlled treatment study of sustained-release lithium carbonate. Outcome measures included gambling severity, mood, anxiety, and impulsivity scales. RESULTS: Pathological gambling patients with bipolar spectrum disorders significantly improved while taking sustained-release lithium carbonate compared to placebo on total pathological gambling scores on the Yale-Brown Obsessive Compulsive Scale, including both thoughts/urges and behavior, as well as on the Clinical Global Impression severity of pathological gambling scale. Affective instability (the Clinician-Administered Rating Scale for Mania score) was also lower in the group treated with sustained-release lithium carbonate compared to placebo. Ten (83%) of 12 completers were rated as responders in the sustained-release lithium group versus five (29%) of 17 in the placebo group. Of note, improvement in gambling severity was significantly correlated with improvement in mania ratings. CONCLUSIONS: Sustained-released lithium may be an effective treatment in reducing both gambling behavior and affective instability in pathological gamblers with bipolar spectrum disorder. This study highlights the need to identify subgroups of pathological gambling patients with bipolar spectrum conditions because this may have important treatment implications.

Imaging monetary reward in pathological gamblers.

We acquired two 18F-deoxyglucose positron emisssion tomography (PET) scans on seven unmedicated pathological gamblers, at least 7 days apart. Following an injection of 5 mCi FDG, subjects carried out a computer blackjack task for 35 min under two different reward conditions: monetary reward and computer game points only. Relative FDG metabolic rate was obtained from regions of interest in the prefrontal cortex, cingulate, striatum and visual cortex. Monetary reward blackjack was associated with significantly higher relative metabolic rate in the primary visual cortex (Brodmann area 17), the cingulate gryus (Brodmann area 24), the putamen and prefrontal areas 47 and 10, compared to blackjack playing for points only. No area tested showed a significant decrease. This pattern suggests heightened limbic and sensory activation in the gambling for money condition with increased emotional valence and greater risk and reward, and confirms the salience of monetary reward in the development of pathological gambling.

Pharmacological treatments of pathological gambling.

Medication treatment studies have demonstrated short-term efficacy of various SRIs, opioid antagonists, and mood stabilizers in sub-samples of adult treatment seeking pathological gamblers. Pathological gambling is frequently comorbid with bipolar spectrum disorders, substance abuse/dependence, and attention-deficit/hyperactivity disorder (ADHD), and comorbidity may influence treatment response in pathological gambling. This review focuses on recent research examining the treatment of pathological gambling and highlights methodological challenges for future studies.

Nefazodone treatment of pathological gambling: a prospective open-label controlled trial.

BACKGROUND: Pathological gambling is a disabling and highly prevalent impulse-control disorder not otherwise specified (NOS). According to the hypothesis of abnormal serotonin function in the pathophysiology of poor impulse control and pathological gambling, we assessed the efficacy and tolerability of nefazodone, a 5-HT antagonist reported to be effective in other impulse-control disorders NOS, in the treatment of pathological gambling. METHOD: Fourteen outpatients who met DSM-IV criteria for pathological gambling were enrolled in a prospective 8-week open-label oral nefazodone trial. Nefazodone was initiated at 50 mg/day and titrated upward to a maximum of 500 mg/day based on patient's response and side effects, with a minimum daily dose of 100 mg. Improvement in gambling was assessed via the pathological gambling modifications of the Yale-Brown Obsessive Compulsive Scale (PG-YBOCS), the Clinical Global Impressions-Improvement scale (PG-CGI-I), and self-rated gambling scales. Response was defined a priori as both a 25% reduction in PG-YBOCS score and a score of 1 (very much improved) or 2 (much improved) on the PG-CGI-I scale. RESULTS: Twelve subjects completed the study, and 2 subjects were early dropouts who did not receive the minimum required dose. Significant improvements were noted in all gambling outcome measures, as well as in depression and anxiety ratings (which did not significantly correlate with gambling reduction). Nine (75%) of 12 patients were rated as responders according to a priori criteria. Side effects (dry mouth and sedation) of moderate severity occurred in 4 subjects. CONCLUSION: These preliminary results suggest that nefazodone may be effective in reducing symptoms of pathological gambling and is well tolerated.

Treatment of depression with comorbid anxiety disorders: differential efficacy of paroxetine versus moclobemide.

To compare the efficacy and tolerability of moclobemide versus paroxetine for the treatment of depression with comorbid anxiety disorders. Outpatients fulfilling DSM-III-R criteria for major depression or dysthymia and for a co-occurring comorbid anxiety disorder (panic disorder, generalized anxiety disorder or obsessive-compulsive disorder) after a 1-week run-in phase were randomly assigned to open-label moclobemide (300-600 mg/day) or paroxetine (20-40 mg/day) for 4 months. Primary criterion for response was a 50% score reduction from baseline on Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scores. Mean changes in Clinical Global Impressions Severity of Illness and Improvement Scales (CGI-I) were also used to evaluate treatment response. Of the 123 patients included in the study, 65 were randomly assigned to moclobemide and 58 to paroxetine. At study end, the two treatment groups did not differ significantly in terms of proportion of responders. Treatment group differences emerged when comorbid anxiety diagnoses were considered. In patients with comorbid panic disorder, paroxetine was superior to moclobemide in improving both anxiety and depression (five patients out of 18 in the moclobemide group and nine out of 14 in the paroxetine group were rated as responders according to CGI-I, P = 0.04). Neither medication was superior in treating comorbid generalized anxiety disorder. These findings indicate that both moclobemide and paroxetine are effective for treatment of depression with comorbid anxiety disorders. However, in the subgroup with comorbid panic disorder, paroxetine is more effective than moclobemide in reducing both depressive and anxiety symptoms.

Psychopharmacology of anxiety disorders.

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.

Positron emission tomography imaging of risperidone augmentation in serotonin reuptake inhibitor-refractory patients.

We studied 15 nondepressed patients with obsessive-compulsive disorder (OCD) who were nonresponders to serotonin reuptake inhibitors with an additive trial of risperidone. Positron emission tomography with (18)F-deoxyglucose and magnetic resonance imaging was obtained at baseline and following 8 weeks of either risperidone or placebo in a double-blind parallel group design. Risperidone treatment was associated with significant increases in relative metabolic rate in the striatum, cingulate gyrus, the prefrontal cortex, especially in the orbital region, and the thalamus. Four of 9 patients who received risperidone showed clinical improvement (CGI score of 1 or 2 at 8 weeks) while none of the 6 patients who received placebo showed improvement. Patients with low relative metabolic rates in the striatum and high relative metabolic rates in the anterior cingulate gyrus were more likely to show a clinical response. These metabolic predictors of clinical response are consistent with earlier PET studies showing similar prediction when either neuroleptics or serotonin reuptake inhibitor treatments are administered individually. Our results are consistent with a frontostriatal circuit change related to both dopaminergic and serotonergic systems and with the presence of psychopharmacological subtypes within OCD.

Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study.

This double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 wk of risperidone augmentation of serotonin reuptake inhibitor (SRI) treatment in adult subjects with treatment-resistant obsessive-compulsive disorder (OCD) (failure of at least two SRI trials). Sixteen adult treatment-resistant OCD patients were randomly assigned to augmentation with 8 wk of either risperidone (n=10) (0.5-3.0 mg/d) or placebo (n=6) following at least 12 wk of SRI treatment. Four patients on risperidone (40%) and none (0%) on placebo were responders with both a Clinical Global Impression - Improvement (CGI-I) score of 1 or 2 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease >/=25%. Risperidone was generally well tolerated: there were 3 dropouts, 1 on risperidone and 2 on placebo. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation. Risperidone may be an effective and well-tolerated augmentation strategy in treatment-resistant OCD subjects, but larger sample size studies are required to demonstrate this.