Brian A. Fallon

Randomized sham-controlled trial of repetitive transcranial magnetic stimulation in treatment-resistant obsessive-compulsive disorder

In open trials, 1-Hz repetitive transcranial magnetic stimulation (rTMS) to the supplementary motor area (SMA) improved symptoms and normalized cortical hyper-excitability of patients with obsessive-compulsive disorder (OCD). Here we present the results of a randomized sham-controlled double-blind study. Medication-resistant OCD patients (n=21) were assigned 4 wk either active or sham rTMS to the SMA bilaterally. rTMS parameters consisted of 1200 pulses/d, at 1 Hz and 100% of motor threshold (MT). Eighteen patients completed the study. Response to treatment was defined as a > or = 25% decrease on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Non-responders to sham and responders to active or sham rTMS were offered four additional weeks of open active rTMS. After 4 wk, the response rate in the completer sample was 67% (6/9) with active and 22% (2/9) with sham rTMS. At 4 wk, patients receiving active rTMS showed on average a 25% reduction in the YBOCS compared to a 12% reduction in those receiving sham. In those who received 8-wk active rTMS, OCD symptoms improved from 28.2+/-5.8 to 14.5+/-3.6. In patients randomized to active rTMS, MT measures on the right hemisphere increased significantly over time. At the end of 4-wk rTMS the abnormal hemispheric laterality found in the group randomized to active rTMS normalized. The results of the first randomized sham-controlled trial of SMA stimulation in the treatment of resistant OCD support further investigation into the potential therapeutic applications of rTMS in this disabling condition.

An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder

The symptom overlap between posttraumatic stress disorder (PTSD) and other pharmacotherapy-responsive disorders suggests that pharmacotherapy might be effective. Nevertheless, of the eight published placebo-controlled trials investigating the pharmacotherapy of PTSD, only four found statistically significant efficacy for the treatment being studied. This literature possesses a number of methodologic limitations, including the fact that most studies have been conducted with war veterans, who may constitute a more treatment-refractory population. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in some or all core PTSD symptoms (reexperiencing, avoidance, numbing, and hyperarousal). The authors hypothesized that paroxetine might be effective in PTSD, based on findings of its particular efficacy for anxiety and agitation in studies of depressed patients. The study presented here summarizes a 12-week, open-label trial of paroxetine among patients with noncombat-related, chronic PTSD. Outcome was assessed by an independent evaluator, the treating physician, and the patient, with the use of established rating scales for depression, anxiety, general symptoms, and PTSD core symptoms. A repeated-measures analysis of variance revealed highly significant improvement in all three symptom clusters, as well as in associated anxiety, depressive, and dissociative symptoms, with 11 of 17 (65%) patients rated as much or very much improved. The mean reduction in PTSD symptom scores was 48%. Exploratory analyses revealed that cumulative childhood trauma was negatively correlated with pharmacotherapy response (r = -0.52, p = 0.03). There was also significant variation in the time course of response across symptom clusters, which is suggestive of multiple mechanisms of response. Because paroxetine seems a highly promising treatment for all three symptom clusters of PTSD, a placebo-controlled clinical trial is warranted.

Imipramine in the treatment of social phobia

We report the results of an 8-week open trial of imipramine in 15 patients with social phobia. Nine patients completed the trial; six dropped out early because of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was 15% and 18% for the intent-to-treat and completer groups, respectively; the overall response rate (based on the Clinical Global Impression Scale of 1 or 2, very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The results from this open trial do not support the efficacy of imipramine as a treatment for social phobia.

Fluoxetine for Hypochondriacal Patients Without Major Depression

Hypochondriasis without concomitant depression is often considered to be unresponsive to pharmacotherapy. Given marked similarities between hypochondriasis and obsessive-compulsive disorder, we decided to conduct an open trial of high-dose fluoxetine for patients with DSM-III-R hypochondriasis who did not meet criteria for major depression. Ten of 16 patients were much improved at the end of 12 weeks. A comparison of baseline and week 12 scores by the use of a paired-samples t-test revealed a statistically significant reduction in hypochondriacal concerns, as measured by the Heightened Illness Concern Clinical Global Impression Severity scale, the Whiteley Index of Hypochondriasis, and the Heightened Illness Concern Questionnaire. These results suggest that fluoxetine may be a useful therapy for hypochondriacal patients without marked depressive features--a group previously considered to be treatment refractory.

Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders

In addition to being effective in depressive disorders, monoamine oxidase inhibitors (MAOIs) have been shown to be effective in controlled studies of patient with panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, posttraumatic stress disorder (PTSD) and borderline personality disorder. Uncontrolled case reports have noted MAOI efficacy in obsessive‐compulsive disorder (OCD), trichotillomania, dysmorphophobia and avoidant personality disorder. Reversible inhibitors of MAO‐A (RIMAs) appear safer than the classical irreversible MAOIs since they have less potential to increase blood pressure. They have not been studied as yet, however, in most of the conditions responsive to MAOIs. If RIMAs are found effective in these disorders, they would probably achieve wider use than MAOIs because they are safer and tend to cause fewer side effects.

Buspirone in social phobia

The novel anxiolytic agent buspirone has been shown to be effective in generalized anxiety disorder, but its utility in phobic disorders is less clear. We examined its efficacy in social phobia in a 12-week open trial. Twenty-one patients who met DSM-III-R criteria for social phobia and who did not respond to 1 week of single-blind placebo were treated with buspirone, and 17 completed a minimum of 2 weeks of treatment. Twelve of these 17 patients met criteria for the generalized subtype of social phobia. At week 12, 8 (47%) of the 17 patients were rated much to very much improved in social phobia symptoms on the Clinical Global Impression Scale. Of the 12 patients who were able to tolerate a dose of 45 mg/day or more, 9 (67%) were at least much improved. Significant improvement was noted on measures of social anxiety and avoidance of social situations. Ratings of generalized anxiety and depression, which were low at baseline, did not change significantly during treatment. The results suggest that buspirone may have modest efficacy in the treatment of social phobia, but confirmation in a placebo-controlled trial is required.

Inflammation and central nervous system Lyme disease

Lyme disease, caused by the bacterium Borrelia burgdorferi, can cause multi-systemic signs and symptoms, including peripheral and central nervous system disease. This review examines the evidence for and mechanisms of inflammation in neurologic Lyme disease, with a specific focus on the central nervous system, drawing upon human studies and controlled research with experimentally infected rhesus monkeys. Directions for future human research are suggested that may help to clarify the role of inflammation as a mediator of the chronic persistent symptoms experienced by some patients despite antibiotic treatment for neurologic Lyme disease.

PET tracers for the peripheral benzodiazepine receptor and uses thereof

The peripheral benzodiazepine receptor (PBR) is expressed on the outer mitochondrial membrane of activated microglia and is implicated in the pathophysiology of a variety of central nervous system and peripheral diseases. The abundant receptor concentration makes PBR a potential biomarker and an attractive target for quantification in vivo using positron emission tomography. PBR can be an important target for monitoring disease progression, for evaluating the effect of therapy, and for investigating new treatment modalities. PBR is also emerging as a potential target in the treatment of neuroinflammatory and neuropsychiatric disorders. Here, we review the positron emission tomography radioligands employed for imaging PBR in living brain and their applications.

Pharmacotherapy of somatoform disorders

OBJECTIVE This paper reviews the published literature on the pharmacologic management of somatoform disorders. METHODS Using Medline, the author identified all articles published between 1970 and 2003 on this topic, selecting the best-designed studies for inclusion. RESULTS The review reveals that patients with the obsessional cluster of somatoform disorders (hypochondriasis and body dysmorphic disorder [BDD]) respond well to serotonin reuptake inhibitors (SRIs). Less is known about the pharmacologic responsiveness of patients with the primarily somatic cluster of somatoform disorders (somatization, pain), a patient group that is common in the health providers office. CONCLUSIONS Improvements in the design of future clinical trials are needed. A particular focus needs to be applied to study the neglected area of the pharmacologic treatment of syndromal and subsyndromal somatization and pain disorders.

Modulation of motor cortex excitability in obsessive-compulsive disorder: An exploratory study on the relations of neurophysiology measures with clinical outcome

Low-frequency repetitive transcranial magnetic stimulation (rTMS) to supplementary motor area (SMA) showed clinical benefit in obsessive-compulsive disorder (OCD). Here we tested whether clinical improvement was associated with enhanced cortical inhibition as measured by single and paired-pulse TMS variables. In 18 OCD patients receiving 4 weeks of either active or sham rTMS in a double-blind randomized trial, we assessed bilateral resting and active motor thresholds (RMT and AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested correlations between changes in Yale-Brown Obsessive Compulsive Scale-Self-report (Y-BOCS-SR), Clinical Global Impression-Severity subscale (CGI-S) and cortical excitability measures. Active rTMS increased right hemisphere RMT whose change correlated with Y-BOCS-SR improvement. Baseline RMT hemispheric asymmetry, defined as the difference between left and right hemispheres RMT, and its normalization after active rTMS correlated with Y-BOCS-SR and CGI-S improvements. Active rTMS also increased right hemisphere SICI whose change correlated with Y-BOCS-SR and CGI-S at week 4, and with normalization of baseline RMT hemispheric asymmetry. Treatment-induced changes in cortical excitability measures are consistent with an inhibitory action of SMA rTMS on dysfunctional motor circuits in OCD. Correlations of neurophysiology measures with therapeutic outcome are supportive of the role of SMA in the modulation of OCD symptoms.