Pinhas N. Dannon

Topiramate versus fluvoxamine in the treatment of pathological gambling : A randomized, blind-rater comparison study

Pathologic gambling (PG) is a highly prevalent and disabling impulse control disorder. Recent studies have demonstrated that PG patients respond well to treatment with SSRIs, mood stabilizers, and opioid antagonists. These findings support the idea that PG and other disorders of impulse control may be conceptualized as part of the obsessive-compulsive spectrum disorders. Pilot studies have shown topiramate to be effective in the treatment of specific disorders of impulse control. The aim of the study is to compare the effectiveness of topiramate versus fluvoxamine in the treatment of PG. Thirty-one male PGs were assigned in a randomized fashion to receive either topiramate (15/31) or fluvoxamine (16/31) pharmacotherapy for 12 weeks. A comprehensive psychiatric diagnostic evaluation was performed on all patients, and all patients were evaluated for symptoms of gambling, depression, and anxiety using the South Oaks Gambling Screen, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Yale-Brown Obsessive Compulsive Symptoms Scale, and the Clinical Global Impression-Improvement Scale. The rating scales were administered at baseline and at the 12-week endpoint. In addition, the patients completed self-report questionnaires about their demographic status. Twelve of the 15 patients from the topiramate group completed the 12-week treatment. Nine of the 12 topiramate completers reported full remission of gambling behavior, and 3 completers had a partial remission. The CGI-improvement score was significantly better for the topiramate group at the 12-week visit as compared with baseline (F = 10.5, P < 0.01, df = 2,31). In the fluvoxamine treatment group 8/16 patients completed the study, and 6/8 fluvoxamine completers reported a full remission, and the remaining 2/8 fluvoxamine completers reported a partial remission. The fluvoxamine group showed improvement in the CGI-improvement score at week 12, although this difference was not significant (F = 3.7, P < 0.08, df = 2,31). Topiramate and fluvoxamine monotherapy may be effective in the treatment of pathologic gambling.

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non‐surgical stimulation of relatively deep brain areas. This is the first double‐blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS‐21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS‐21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12‐week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

Sustained-release bupropion versus naltrexone in the treatment of pathological gambling : A preliminary blind-rater study

Background: Pathological gambling (PG) is a relatively common and highly disabling impulse control disorder. A range of psychotheraputic agents, including selective serotonin reuptake inhibitors, mood stabilizers, and opioid antagonists, has been shown to be effective in the treatment of PG. The use of selective serotonin reuptake inhibitors and opioid antagonists for PG is consistent with the observation that PG shares features of both the obsessive-compulsive spectrum disorders and addictive disorders. The aim of the study is to compare the effectiveness of sustained-release bupropion versus naltrexone in the treatment of PG. Methods: Thirty-six male pathological gamblers were enrolled in our study. A comprehensive psychiatric diagnostic evaluation was performed at baseline on all patients, and patients were screened for symptoms of gambling, depression, and anxiety using the South Oaks Gambling Screen, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression-Severity Scale. In addition, the patients completed self-report questionnaires about their demographic status. Patients were randomized in 2 groups and received either naltrexone (n = 19) or sustained-release bupropion (n = 17) for 12 weeks in a parallel fashion. Treatment response was monitored using the Clinical Global Impression-Improvement Scale which was performed at weeks 2, 4, 8, and 12. Patients were also assessed for the presence of gambling behavior via an unstructured interview, which was also performed at weeks 2, 4, 6, 8, and 12. Raters were blind to the study treatment. Results: The majority of patients responded well to the drug treatment. Twelve of 17 patients in the sustained-release bupropion group completed the 12-week study, and 13 of 19 naltrexone patients completed the study. Nine (75%) of the 12 completers were rated as full responders in the sustained-release bupropion group versus 10 (76%) of 12 in the naltrexone group. Three (25%) of 12 completers in the bupropion group were rated as partial responders. In the naltrexone group, 3 (23%) of 13 completers were rated as partial responders. Full response was defined as the absence of gambling for a 2-week duration together with improvement on the Clinical Global Impression-Improvement Scale. Partial response was defined as a decrease in the frequency of gambling behavior and a decrease in the amount of money spent on gambling. Conclusion: This preliminary study shows that sustained-release bupropion may be effective as naltrexone in the treatment of PG. Further studies are needed to confirm our findings.

Go–no-go performance in pathological gamblers

Previous neuropsychological studies demonstrated various deficits of impulse control in pathological gamblers (PGs). However, there are limited data available on response-inhibition impairment among PGs. The present study attempted to assess response inhibition in untreated PGs (N=83), in comparison with normal subjects (N=84). Go/no-go and target-detection conditions of a computerized task were used as a measure of response-inhibition ability. A repeated measures analysis of covariance (ANCOVA-RM) was used with response time, variability of response time, and number of false alarms and misses as dependent measures; group (PG and controls) as the between-subjects measure; condition (target detection or go/no-go) and time slice (first and second in each condition) as repeated measures within-subject factors; and educational level as a covariate. Our results showed that PGs were significantly more impaired in both target detection and go/no-go task performance than controls. The PGs had significantly more false alarms and misses than controls, and they were slower and less consistent in their responses.

Pindolol augmentation in patients with treatment-resistant panic disorder: A double-blind, placebo-controlled trial.

The objective of this study was to determine the efficacy of pindolol as an augmentor of fluoxetine in treatment-resistant panic disorder (PD). Twenty-five outpatients having PD with or without agoraphobia were included. These patients had not responded to two different trials with antidepressants and an 8-week trial of fluoxetine 20 mg/day. Treatment-resistant PD was defined as a less than 20% reduction in score on the Panic Self-Questionnaire (number of attacks per week) (PSQ) and the Clinical Anxiety Scale With Panic Attacks (CAS+PA). These patients continued to receive fluoxetine 20 mg/day and were randomly assigned to additionally receive either pindolol (2.5 mg three times daily) or placebo for the following 4 weeks. Evaluations were performed weekly using the Hamilton Rating Scale for Anxiety, the Hamilton Rating Scale for Depression (HAM-D), the CAS+PA, the NIMH Anxiety Scale, the PSQ, and the Clinical Global Impression Scale. The data were analyzed using a repeated-measures analysis of variance (ANOVA) and a t-test for independent samples. Patients treated with the combination of pindolol and fluoxetine (N = 13) demonstrated a significant improvement over the patients treated with fluoxetine and placebo on all rating scales, with the exception of HAM-D. The statistical differences were shown using the repeated-measures ANOVA (baseline, week 2, week 4) and also with t-tests from the second week of the trial. These preliminary results demonstrate that pindolol has an augmenting effect on fluoxetine in patients with treatment-resistant PD.

Pathological gambling: an update on neuropathophysiology and pharmacotherapy.

Neurobiological research has shown the potential involvement of serotonergic, dopaminergic and opioid dysfunction in the pathophysiology of pathological gambling. In this review, we present current theories of the neuropathology of pathological gambling, paying particular attention to the role of the neural circuitry underlying motivation, reward, decision-making and impulsivity. This review also presents a literature review of current pharmacological treatment strategies for pathological gambling, such as SSRIs, opioid receptor antagonists, anti-addiction drugs and mood stabilizers, and also discusses the role of nonpharmacological interventions.A hypothetical model of the clinical subtypes of pathological gambling is presented, e.g. the impulsive subtype, the obsessive-compulsive subtype and the addictive subtype. This model attempts to integrate current knowledge in the field of pathological gambling regarding neuropathology, psychiatric co-morbidity, family history, genetics, course of illness, gender and response to pharmacological treatment. Finally, it is proposed that the existence of possible clinical subtypes of pathological gambling may provide a potential framework for matching the various subtypes with specific pharmacotherapies.

Topiramate for the treatment of kleptomania: A case series and review of the literature

Kleptomania--the inability to resist the impulse to steal objects, not for personal use or monetary gain--is currently classified in psychiatric nomenclature as an impulse control disorder. There is no standard pharmacologic therapy for this disorder. If kleptomania was considered a form of obsessive-compulsive disorder, treatments used for this spectrum, including serotonin reuptake inhibitors (SSRI), other antidepressants, opioid receptor antagonist medications, and mood stabilizers, could be logically tested. Topiramate is currently used for the treatment of patients with affective and compulsive eating disorders. This report documents three kleptomanic patients who responded well to topiramate given either alone or in combination with SSRIs.

Risk-taking decisions in pathological gamblers is not a result of their impaired inhibition ability

This work investigates whether inhibition impairments influence the decision making process in pathological gamblers (PGs). The PG (N=51) subjects performed the Iowa Gambling Task (IGT as the measure of the decision making process) and two tests of inhibition: the Stroop (interference inhibition), and the Go/NoGo (response inhibition), and were compared with demographically matched healthy subjects (N=57). Performance in the IGT block 1 and block 2 did not differ between the groups, but the differences between the PGs and healthy controls began to be significant in block 3, block 4 and block 5. PGs learned the IGT task more slowly than the healthy controls and had non-optimal outcomes (more disadvantageous choices). Impaired IGT performance in PGs was not related to an inhibition ability measured by the Stroop (interference response time) and the Go/NoGo (number of commission errors) parameters. Further controlled studies with neuroimaging techniques may help to clarify the particular brain mechanisms underlying the impaired decision making process in PGs.

A naturalistic long-term comparison study of selective serotonin reuptake inhibitors in the treatment of panic disorder.

Objectives: Selective serotonin reuptake inhibitors (SSRIs) are currently considered as the first drug of choice in the treatment of panic disorder (PD). The aim of this long-term, naturalistic comparison study was to compare 4 SSRIs with respect to tolerability and treatment outcome of PD. Outcome measures included relapse rates and adverse effects. Methods: Two hundred patients with PD were enrolled in our study. All subjects met DSM-IV criteria for PD or PD with agoraphobia (PDA). All patients were assigned to receive SSRI monotherapy for 12 months with either citalopram (n = 50), fluoxetine (n = 50), fluvoxamine (n = 50), or paroxetine (n = 50) in a randomized, nonblinded fashion. Both the treating psychiatrist and the patients were not blind to the assigned treatment, but the clinician raters were blind to the study medication. The study design allowed for assignment of a particular SSRI as indicated according to the clinical judgment of the study psychiatrists. The Panic Self-Questionnaire, which is a self-report scale, was administered at baseline and then once per month during the duration of the 12-month study. The visual analog scale and the Clinical Global Impression Scale were administered at baseline and then once per month during the period of the study. Reports of sexual dysfunction were assessed using a nonstructured clinical interview at monthly visits. The body weight of study subjects was measured at baseline, and then at the 12th month visit end point. Results: Of 200 patients who entered the study, 127 patients (63.5%) completed the full 12-month protocol. Retention rates were highest for paroxetine (76% [38/50]), intermediate for citalopram (68% [34/50]) and fluvoxamine (60% [30/50]), and lowest for fluoxetine (50% [25/50]). Patients who completed the 12-month protocol responded favorably to the study treatment. The paroxetine and the citalopram groups had significantly lower rates of panic symptoms as measured at visits on weeks 4 and 8. At visits on months 3, 6, 9, and 12, however, there were no statistically significant differences between the 4 groups in relapse rates (defined as the occurrence of 1 or more panic attacks during the previous week of treatment) (F1,127 = 0.17; P = 0.13 [not statistically significant]). At the 12th month end point, patients in all 4 treatment groups had a statistically significant increase in body weight. Body weight among the study population increased by 6.1 + 4.9 kg from a mean weight of 72.4 + 7.3 kg at the onset of treatment. Reports of sexual adverse effects at the 12th month visit were similar in the citalopram, fluoxetine, and paroxetine groups, but the fluvoxamine patient group reported fewer sexual adverse effects at the 12th month visit. Conclusions: Most of our PD patients responded well to 12-month treatment with either citalopram, fluoxetine, fluvoxamine, or paroxetine, and the overall response rate was equal after the first 4 weeks of treatment. Although patients treated with paroxetine had the lowest dropout rates during the initiation phase, they had the highest rate of adverse effects as measured at the 12th month visit. Conversely, patients in the fluvoxamine group had the highest dropout rate (which was primarily caused by adverse effects in the initiation phase of treatment.); however, patients who were able to tolerate fluvoxamine throughout the full course of the study were observed to have lower rates of sexual dysfunction and weight gain compared with patients treated with the other agents. Overall, when measured at the 12th month visit, monotherapy with paroxetine and citalopram was associated with a higher rate of sexual adverse effects than was treatment with fluoxetine or fluvoxamine. In addition, monotherapy with paroxetine, citalopram, and fluoxetine seemed to cause more weight gain than did treatment with fluvoxamine.

Deep TMS in a resistant major depressive disorder: a brief report

Introduction: Repetitive transcranial magnetic stimulation (rTMS) has proven effective. Recently, a greater intracranial penetration coil has been developed. We tested the efficacy of the coil in the treatment of resistant major depression. Methods: Our sample included seven patients suffering from major depression who were treated using Brainsways H1‐coil connected to a Magstim rapid 2 stimulator. Deep TMS treatment was given to each patient in five sessions per week over a period of 4 weeks. Patients were treated with 120% intensity of the motor threshold and a frequency of 20 HZ with a total of 1,680 pulses per session. Results: Five patients completed 20 sessions: one attained remission (Hamilton Depression Rating Scale (HDRS)=9); three patients reached a reduction of more than 50% in their pre‐treatment HDRS; and one patient achieved a partial response (i.e., the HDRS score dropped from 21 to 12). Average HDRS score dropped to 12.6 and average Hamilton Anxiety Rating Scale score dropped to 9.Two patients dropped out: one due to insomnia and the second due to a lack of response. Discussion: Compared to the pooled response and remission rates when treating major depression with rTMS, deep TMS as used in this study is at least similarly effective. Still, a severe limitation of this study is its small sample size, which makes the comparison of the two methods in terms of their effectiveness or side effects impossible. Greater numbers of subjects should be studied to achieve this aim. Conclusions: An H1 deep TMS coil could be used as an alternative treatment for major depressive disorder. Depression and Anxiety, 2010.