George W. Arana

A controlled trial of daily left prefrontal cortex TMS for treating depression

BACKGROUND Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham. METHODS Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD. RESULTS Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (chi(2) = 6.42, p <.01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham. CONCLUSIONS Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

Psychotic features and illness severity in combat veterans with chronic posttraumatic stress disorder

BACKGROUND Psychotic symptoms may be present in up to 40% of patients with combat-related posttraumatic stress disorder (PTSD). In this study, we hypothesized that severity of psychotic symptoms would also reflect severity of PTSD symptoms in patients with well-defined psychotic features. METHODS Forty-five Vietnam combat veterans with PTSD but without a primary psychotic disorder diagnosis underwent a Structured Clinical Interview for DSM-III-R with Psychotic Screen, and the Clinician Administered PTSD Scale (CAPS). Patients identified as having psychotic features (PTSD-P), (n = 22) also received the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). RESULTS There was a significant positive correlation between the CAPS and PANSS global ratings (p < .001) and the HDRS and PANSS (p < .03) in the PTSD-P patients. Many CAPS and PANSS subscales also demonstrated significant intercorrelations; however, the CAPS-B subscale (reexperiencing) and the PANSS positive symptom scale were not correlated, suggesting that psychotic features may not necessarily be influenced or accounted for by more severe reexperiencing symptoms. Fifteen (68%) of the PTSD-P patients had major depression (MDD). Both CAPS and PANSS ratings were significantly higher in the PTSD-P patients with comorbid MDD. CONCLUSIONS As postulated, patients with more severe psychosis ratings are likely to have more severe PTSD disease burden if psychotic features are present. This study further documents the occurrence of psychotic features in PTSD that are not necessarily due to a primary psychotic disorder, suggesting that this may be a distinct subtype; however, a significant interaction likely exists between PTSD, depression, and psychotic features.

Low frequency daily left prefrontal rTMS improves mood in bipolar depression: a placebo-controlled case report

Preliminary studies in unipolar depression indicate that daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) reduces symptoms of depression. rTMS treatment of depression occurring in the setting of bipolar disorder has been less well studied. To assess the efficacy and toxicity of rTMS in the depressed phase of bipolar disorder, we treated a man with bipolar disorder who was known to develop hypomania and mania with conventional antidepressants. A 47 year old man with Bipolar Disorder type 1, depressed phase, was entered into a double‐blind parallel treatment trial of left prefrontal rTMS. He was randomized to receive left prefrontal rTMS at low frequency (5 Hz) for 2 weeks, which was then followed by an open phase. The patients Hamilton Depression scores decreased 44 per cent across the first 2 weeks. In an open extension, his mood further improved over another 2 weeks and he was gradually tapered from rTMS treatments. He had no side effects. Importantly, he did not develop mania, as had occurred with all prior antidepressant trials. After several months he experienced a recurrence of depressive symptoms, was retreated, and re‐responded. Further studies are warranted to investigate the optimum dose, duration, location and frequency of rTMS treatments for the depressed phase of bipolar disorder.

The impaired physician: A medical and social dilemma ☆ ☆☆

Psychological and emotional impairment among physicians represents a serious, widespread, and difficult problem. For unclear reasons, it has been problematic to effectively identify and treat this group of professionals whose performance is so intimately associated with the health and wellbeing of the general population. The severity of the problem, the resistance to treatment which seems evident from the data presented, and the fact that most of the conditions afflicting physicians are treatable and reversible, compels us to seek a viable solution. Diligence in the pursuit of understanding and correction of the dilemma is a social and personal imperative.

Plasma corticosterone and cortisol following dexamethasone in psychiatric patients

Radioimmunoassays of cortisol (F) and corticosterone (B) were carried out in 133 plasma specimens, obtained at 0800 or 1600 h on the day following administration of dexamethasone (1.0 mg), from 69 patients admitted to a psychiatric inpatient service, to test suggestions that assays of B might complement those of F in the dexamethasone suppression test (DST) in a psychiatric setting. The overall correlation between F and B was +0.80. Concentrations of B averaged 5-8% those of F. We found close agreement (80-85%) between positive (F greater than or equal to 4.5 micrograms/dl) and negative DST results for both steroids assayed by radioimmunoassay at a criterion of greater than or equal to 1.5 ng/ml for B, as well as a reasonable compromise between sensitivity and specificity of the B-DST at that criterion. Post-dexamethasone samples obtained at 1600 h showed somewhat closer agreement between the B-DST and the F-DST than at 0800 h. Inclusion of 0800 h samples added little to the rate of positive results with the F-DST but did add to those of the B-DST by about 10% or more, depending on the criterion selected for a positive B-DST. The rate of positive DSTs among 44 patients who had both steroids assayed at both times was approximately 61%, and the agreement between positive test results among these patients was 92%. In a mixed population of acutely ill, hospitalized patients with various DSM-III diagnoses, but excluding those with medical or pharmacologic contraindications to the DST, high rates of positive DST results were obtained in patients with major depressive disorders (47-58%), with little difference found among those with bipolar, non-bipolar or melancholic characteristics. High rates also were found among manic and other acutely psychotic patients, as well as others with neurotic or characterological diagnoses, but rarely in a small group of chronic schizophrenics. Thus, a positive DST as evaluated with B or F is evidently not specific for cases of major depression, but may be indicative of acute illness, possibly with affective features. The results support suggestions that a steroid suppression test based on corticosterone may be useful to aid in diagnosis of major psychiatric illnesses and might complement or substitute for the F-DST. It may be possible to avoid certain pharmacologic complications in the DST by use of a test based on suppression of B by F rather than by dexamethasone.

Pharmacology of [3H]apomorphine binding to bovine brain tissue

Abstract Activity against high-affinity (nM), and over 80 per cent dopamine (DA)-agonist-displaceable binding of [3H]apomorphine (APO) to a “subsynaptosomal” membrane fraction of bovine caudate nucleus was evaluated using amino-6,7-dihydroxytetralin (ADTN) as a blank. Aporphines with 10,11-catechol and small N-alkyl groups were potent inhibitors ( IC 50 nM ) with parallel inhibition curves (nh = 0.8 to 1.0). For phenethylamines, catechol and amine moieties were important structural requirements; α or β substitution markedly reduced potency. Thus, epinephrine and isoproterenol were weak while DA and its N-methylated congeners were potent; (− )norepinephrine (NE) and fluoro-DAs were intermediate in potency and ( + )NE, other catechols and hydroxylated phenethylamines were virtually inactive; m-tyramine, while weak, was more active than p-tyramine. Other DA agonists [ADTN > lergotrile >N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) > bromocriptine] were active. Neuroleptics competed relatively weakly, with imperfect correspondence to in vivo activities. Stereoselectivity was found with several aporphines, phenethylamines, and antipsychotic drugs. Many other neuropharmacologically active agents, including inhibitors of amine uptake and adrenergic receptors, were inactive. These characteristics strongly suggest that APO interacts with a DA agonist binding site in mammalian brain tissue.

Effects of bupropion sustained-release on sexual functioning and nocturnal erections in healthy men.

Many antidepressants are known to cause adverse sexual effects. Bupropion is an antidepressant with fewer reported adverse sexual effects. Studies of sexual side effects are often confounded by psychiatric and medical conditions affecting sexual function. In this study, the effects of bupropion on subjective and objective sexual functioning were measured in healthy men. Thirteen men without psychiatric or medical illness completed a 2-week, placebo-controlled, double-blind, crossover trial of bupropion sustained-release 300 mg/day. Subjects had a 1-week washout period between trials. Sexual function was measured using a validated, self-administered questionnaire and the RigiScan, an instrument measuring nocturnal penile tumescence and rigidity. No differences were found in self-reported sexual function, number of erections, total erection time, or penile rigidity in subjects taking bupropion compared with those taking placebo or baseline. These findings support that bupropion does not have subjective adverse sexual side effects and does not affect nocturnal erections in healthy men.

Improved high-affinity binding of 3H-apomorphine with a subcellular membrane fraction of mammalian brain tissue

Abstract The binding of low concentrations of [ 3 H](−)apomorphine to preparations of calf and rat forebrain tissue was evaluated. Fractionation of crude homogenates to prepare a membrane fraction (P 4 ) of striatal or caudate homogenates increased the proportion of saturable to total binding from 33% to over 80%, and increased the apparent density of binding sites from 94 to 681 fmol/mg protein. Binding in calf caudate P 4 tissue was protein-dependent and optimal at pH = 7.0 to 7.5, and T = 20 to 25°C; at higher temperatures tissue binding sites appeared to degrade. The half-time of association and dissociation at 22°C were, respectively, 14.0 and 18.5 min; equilibration was complete in 60 min. Kinetic characteristics of high-affinity binding obtained from association and dissociation constants and from saturation isotherms were similar (K d = 2.1 to 3.4 nM). The pharmacology of competition for 3 H-APO suggests selectivity for dopamine-agonist interactions. These results indicate that the P 4 membrane preparation may be useful for the evaluation of dopamine-agonist binding sites or “receptors.”

Procaine administration and behavioral responsivity in post-traumatic stress disorder: a pilot study of tolerability

Procaine, a local anesthetic, selectively activates the anterior limbic region of the brain, including the anterior cingulate, and may produce powerful emotional and other behavioral responses (including psychotic symptoms) in humans. In a pilot study, we administered intravenous procaine and placebo (saline) to nine combat veterans with PTSD at a dose of procaine known to produce significant behavioral responses in healthy subjects (1·38 mg/kg). All but one PTSD patient had mild to moderate, subjective responses to procaine that were statistically elevated on a procaine symptom rating scale (p<0·01) compared with saline. Symptoms that occurred only during the procaine infusion included anxiety or euphoria, auditory and visual hallucinations or illusions, and certain physical symptoms such as paresthesias. Two of the nine patients had specific PTSD reexperiencing symptoms. However, all patients tolerated the procedure well and, in eight of the patients, symptoms resolved within 5–10 min of procaine administration. One patient had possible dissociative symptoms up to 1 h after procaine that resolved without a recurrence. No patient had a persistent exacerbation of PTSD symptoms. This pilot study suggests that procaine may be a feasible pharmacologic probe to test anterior limbic function in PTSD. Copyright

The Effect of Benztropine on Haloperidol-Induced: Dystonia, Clinical Efficacy and Pharmacokinetics

Twenty-nine inpatients with major psychotic disorders were treated for 14 days with a clinician-determined dose of haloperidol and with either benztropine or placebo given by double-blind random assignment on days 1 through 7. No differences were noted in haloperidol mean dose, haloperidol blood levels, or BPRS scores during the first seven days between benztropine (N = 14) and placebo (N = 15) groups. Benztropine-treated patients demonstrated increased dry mouth and diminished sweat and a non-significantly lower rate of dystonia compared to placebo (14% vs. 33%). Dystonic patients were significantly younger than nondystonic patients, but did not differ in haloperidol mean dose or plasma concentration. The effect of benztropine on the incidence of dystonia was consistent with other studies, which, when analyzed together, demonstrate the efficacy of anticholinergic prophylaxis. The relatively low incidence of anticholinergic side effects, coupled with the lack of effect on haloperidol blood levels or antipsychotic efficacy, suggest that moderate doses of benztropine in conjunction with haloperidol are a rational approach for the treatment of acute psychosis in young patients.