Predictors of treatment response in patients with posttraumatic stress disorder.

1. This study examines the relation between baseline clinical characteristics in patients with posttraumatic stress disorder (PTSD) and response to treatment with a reversible monoamine oxidase A inhibitor (RIMA), brofaromine. 2. Data from two comparable, double-blind, placebo-controlled studies of brofaromine in patients with PTSD were combined. Bivariate analyses of variables of interest and outcome were performed. 3. Treatment response was significantly associated with lower baseline scores on the full scale Clinician-Administered PTSD Scale (CAPS) and on CAPS subscales B (re-experiencing) and C (avoidance/numbing), as well as to drug treatment with brofaromine. Placebo response was related to a history of past sexual trauma. 4. Brofaromine may have therapeutic benefit in treating PTSD, with lower baseline levels of reexperiencing and avoidance/numbing and overall less severe PTSD most predictive of outcome.

Brofaromine for social phobia: a multicenter, placebo-controlled, double-blind study.

The safety and efficacy of brofaromine, a reversible and selective monoamine oxidase inhibitor, were examined in a multicenter trial of 102 outpatients with social phobia. After a 1-week placebo washout, subjects were randomly assigned to 10 weeks of treatment with either brofaromine (N = 52) or placebo (N = 50). Brofaromine dosage began at 50 mg/day and was titrated to a maximum of 150 mg/day, depending on treatment response. Brofaromine produced a significantly greater change from baseline in Liebowitz Social Anxiety Scale (LSAS) scores compared with placebo, F(1) = 6.01, p < 0.016. Mean LSAS scores decreased from 81.8 at baseline to 62.6 at endpoint for brofaromine, t = 5.41,p < 0.001, and from 79.8 to 70.7 for placebo, t = 3.66, p < 0.001. Eleven of the 14 brofaromine early terminators discontinued because of adverse experiences, as did 4 of the 17 placebo early terminators. Side effects more common with brofaromine than placebo included insomnia, dizziness, dry mouth, anorexia, tinnitus, and tremor. No clinically significant variations in vital signs or laboratory values were found. The findings are consistent with the clinical efficacy for the treatment of social phobia.

Effects of hormone replacement therapy on the circadian pattern of atherothrombotic risk factors.

Onset of acute atherothrombotic events (acute myocardial infarction, unstable angina, ischemic stroke) exhibit a circadian pattern that parallels the diurnal pattern of endogenous fibrinolytic activity. Hormone replacement therapy in postmenopausal women has been shown to enhance fibrinolytic capacity by lowering plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator inhibitor (tPA) antigen values. We evaluated the impact of 4 weeks of estrogen alone (Premarin 0.625 mg/day) and 2 weeks of estrogen plus progesterone (Provera 2.5 mg/day) on PAI-1 and tPA in 17 postmenopausal women at multiple time points to assess hormone impact on the diurnal pattern of fibrinolytic potential. At baseline, both PAI-1 and tPA exhibited circadian variability. Estrogen alone selectively lowered 8 A.M. PAI-1 (35.8 +/- 7.1 ng/ml at baseline, 19.8 +/- 3.7 ng/ml on estrogen; p = 0.0002 vs baseline). There was no significant change in the noon or 4 P.M. values, and the diurnal pattern was attenuated. The 8 A.M. PAI-1 remained low at 17.1 +/- 3.6 ng/ml (p = 0.0001 vs baseline) with total loss of the circadian rhythm. Estrogen supplementation reduced tPA antigen at all time points, and the diurnal pattern, although blunted, persisted. Addition of progesterone to estrogen did not reverse effects of the estrogen alone phase of either PAI-1 or tPA values. This hormone-associated reduction of PAI-1 was observed despite increased triglycerides, a known inducer of PAI-1 levels. These observations suggest that hormone replacement therapy may protect postmenopausal women from excess early morning acute ischemic events.

Relationship between early side effects and therapeutic effects of clomipramine therapy in obsessive-compulsive disorder.

Early adverse effects of a drug may be a manifestation of individual differences in drug metabolism or of different pathologic processes. These differences may influence therapeutic responsiveness. Using data from Ciba-Geigy's multicenter 10-week clinical trial, we studied the relationship between early side effects and subsequent therapeutic response to clomipramine (CMI) in obsessive-compulsive disorder. We used tabular analyses and multiple regression to evaluate associations between early complaints and change in score on the Yale-Brown Obsessive-Compulsive Scale. We also evaluated whether early complaints were drug related (i.e., true side effects). It appeared that dry mouth, constipation, dizziness, insomnia, male impotence, nervousness, palpitation, and tremor reported during the first 4 weeks were predictive of good response to CMI. Myoclonus and tinnitus appeared weakly associated with treatment success. Most of these complaints were reported more by the CMI group than the placebo group, and more during CMI treatment than before. The more common complaints may reflect an individual's ability to metabolize CMI appropriately so that adequate therapeutic blood levels are attained. The less common complaints may reflect a sensitivity to CMI's serotonergic actions.

Are insulin and proinsulin independent risk markers for premature coronary artery disease ?

Controversy persists about whether hyperinsulinemia and hyperproinsulinemia are independent risk markers for coronary atherosclerosis. A common limitation of most previous studies has been imprecise categorization of disease status in normal and coronary artery disease (CAD) groups. We assessed the relationship of pancreatic beta-cell secretory products and premature CAD in a case-control study of 134 nondiabetic subjects, aged < or = 55 years old, carefully defined for CAD status by catheterization and/or thallium stress studies. Case patients comprised 66 patients with premature CAD, and control subjects (non-CAD group) included 68 patients without CAD but with traditional CAD risk factors and chest pain and/or abnormal electrocardiograms but normal catheterization and/or thallium stress studies. In addition to the CAD and non-CAD group comparison, both groups were compared with a reference group of 27 mixed lean and obese control volunteers. All CAD and non-CAD patients had a 3-h 75-g oral glucose tolerance test with measurement of fasting and post-glucose load immunoreactive insulin (IRI), specific insulin (INS), proinsulin-like material (PI), and C-peptide. Increased fasting insulin and fasting proinsulin levels both were statistically significantly associated with higher odds of being in either the premature CAD and the non-CAD groups when compared with the reference group in a polychotomous logistic regression model (odds ratio of at least 1.20 for a 20% increase in each beta-cell secretory product in both comparisons, P < 0.05). However, increased pancreatic beta-cell secretory hormone levels did not show a statistically significant relative risk for being in the premature CAD group when compared with the non-CAD group. After adjustment for BMI, all statistically significant associations disappeared for IRI, INS, and PI when the odds favoring being in the CAD and non-CAD groups were compared versus the reference group. Furthermore, the odds of being in the premature CAD and non-CAD groups when compared with the reference group were not significantly associated to the ratio of PI to insulin and C-peptide. Thus, although there is a statistically significant association between the odds of having premature CAD with elevated insulin and proinsulin levels compared with the reference group, these findings are equally common in subjects with traditional CAD risk factors without detectable CAD. Furthermore, the association of higher insulin and proinsulin levels with the likelihood of a patient having or not having CAD disappears after adjustment for BMI, suggesting that insulin and proinsulin are not independent risk markers but are primarily dependent on obesity.

Prevention of nitroglycerin tolerance with diuretics.

Tolerance to prolonged nitroglycerin (NTG) may be due to drug-induced intravascular expansion. To test the hypothesis that concomitant diuretics may reduce volume expansions and thus prevent NTG tolerance, we studied 23 healthy volunteers randomized to hydrochlorthiazide or placebo before and during 74-hour continuous NTG exposure. Venodilator response to NTG was tested serially with venous forearm plethysmography. In the preNTG patch phase venodilator response was similar in both the placebo and diuretic groups. Venodilator capacity was compared after "acute" (2-hour) and "chronic" (74-hour) NTG exposure with NTG patches. Attenuation to NTG was seen in the placebo group, but NTG venodilator activity was fully maintained in the diuretic group. These data suggest that diuretics may be helpful in the prevention of NTG tolerance.

Predictors of treatment response in obsessive-compulsive disorder: multivariate analyses from a multicenter trial of clomipramine.

There have been many attempts to find predictors of the therapeutic response to the clomipramine treatment of obsessive-compulsive disorder. The majority of studies have failed to identify such predictors. Possible reasons for this failure include the small sample size of most studies, samples homogeneous with respect to the study factors of interest, and the use of statistical procedures that are insensitive to individual differences or that inadequately control for confounding. We have reanalyzed data from Ciba-Geigy's large, multicenter clinical trial of clomipramine for obsessive-compulsive disorder, using stratification and regression techniques to identify multiple prognostic factors and control for confounders. We assessed the relationship between therapeutic response and baseline measures such as severity of symptoms, type of symptoms (obsessions, compulsions, depression), length of illness, age of onset, and other demographic factors (age, race, and sex). We found age of onset to be a strong predictor of response to clomipramine: people who develop obsessive-compulsive disorder later in life have a better chance of responding than do those who become ill earlier, independent of length of illness. We also found that baseline depression is associated with response, but the association appears to be nonlinear.

Pharmacotherapy of post-traumatic stress disorder with a novel psychotropic.

This was a multicenter, randomized, double-blind, parallel trial conducted in outpatients in three countries. Following screening and placebo washout, patients received brofaromine (a combined MAO-A inhibitor/5-HT transport inhibitor) or placebo in a flexible dosing design. Based upon the CAPS, a standardized post-traumatic stress disorder (PTSD) interview, findings from a cohort involving both subchronic and chronic traumatic stress marginally favored brofaromine over placebo; however, not to a statistically significant degree. With a more conservation definition of the syndrome, employing a primary cohort of patients with PTSD of one year or greater duration, brofaromine significantly reduced PTSD symptoms in comparison with placebo. In all analyses a substantial proportion of patients in both drug and placebo groups remained symptomatic throughout. Findings were supported by an analysis of secondary measures. Brofaromine may be of benefit in the therapy of PTSD.

Serotonergic (5-HT2) mediation of anxiety-therapeutic effects of serazepine in generalized anxiety disorder.

Serotonin 1a and serotonin-2 receptors are implicated in anxiety. Serazepine (CGS-15040A, (R,S)-1,3,4,16b-Tetrahydro-2-methyl-2H,10H-indolo[2,1-c] Pyrazino-[1,2-a][1,4] benzodiazepine-16-carboxylic acid, methyl ester hydrochloride]) is a representative of a novel pentacyclic ring system containing a stabilized indole. In chemical assays it was a highly specific inhibitor of serotonin (5-HT2) binding, and it was active in preliminary preclinical assays of anxiolytic potential. This multicenter trial of CGS-15040A in patients with generalized anxiety disorder demonstrated clinical anxiolytic effects consistent with established preclinical effects. Doses greater than or equal to 10 mg reduced Hamilton Anxiety Scale scores. However, the dose-response relationship was nonlinear. Effects appeared primarily related to the psychic components of anxiety.

Genetic influences on eating attitudes in a normal female twin population.

The Eating Attitudes Test (EAT) and the Eating Disorder Inventory (EDI) were administered to a female volunteer twin population aged 18 to 45 years. Both members of 147 monozygotic (MZ) and 99 dizygotic (DZ) twin pairs completed the questionnaires. Thirty-five subjects scored over the cut-off point of the EAT-26. Interviews of these high-scoring twins and their co-twins identified three subjects with a past history of anorexia nervosa, and three others with a history of a partial syndrome. A heritability value of 41% was obtained for the overall EAT scores, while factor analysis produced a 'dieting' factor with a heritability of 42%. The 'body dissatisfaction' and 'drive for thinness' subscales of the EDI had heritability values of 52 and 44% respectively. The genetic contribution to the variance in body mass index in the twin sample was estimated at 64%. For all the above phenotypes, an environmental model of transmission with heritability constrained to be zero, could be rejected. Conversely, we were unable to reject a purely additive genetic model with shared environmental variance constrained at zero, suggesting that family environment has little or no effect on the transmission of many of these traits.

Lack of rebound during intermittent transdermal treatment with glyceryl trinitrate in patients with stable angina on background beta blocker.

OBJECTIVE: To assess whether intermittent transdermal treatment with glyceryl trinitrate causes clinically significant rebound in patients maintained on beta blockers for stable angina pectoris. DESIGN: Serial treadmill exercise testing in a double blind, randomised, placebo controlled cross over trial. Baseline exercise testing was performed at 0900 and 1100 at visit 1. Transdermal glyceryl trinitrate patches releasing 15 mg/24 h were applied at 2200 the evening before visits 2 and 3, and exercise testing was performed at 0900 the next morning. The patch was removed and replaced with either an identical patch or matching placebo and exercise tests were repeated two hours later. The alternative treatment was given at visit 3. SETTING: Tertiary referral centre. PATIENTS: 14 patients with stable angina pectoris maintained on beta blocker treatment alone. MAIN OUTCOME MEASURES: Time to angina, 1 mm ST segment depression, and total time, together with heart rate, systolic blood pressure, and rate-pressure product. RESULTS: Active treatment improved treadmill performance at 0900 and 1100. Time to angina, time to 1 mm ST segment depression, and total time fell significantly on placebo compared with the 0900 exercise test on active treatment, but were not significantly different to the baseline exercise test either. CONCLUSIONS: Intermittent transdermal treatment with glyceryl trinitrate is not associated with the rebound phenomenon in patients maintained on beta blockers for stable angina pectoris.

A clinical test of noradrenergic involvement in the therapeutic mode of action of an experimental antidepressant.

The noradrenaline (NA) hypothesis of depression is founded primarily on preclinical and clinically indirect evidence. In two three-compartment randomized parallel clinical trials conducted serially, we examined the significance of NA uptake for antidepressant activity. The racemic compound oxaprotiline (hydroxymaprotiline) is a highly specific inhibitor of NA uptake, whereas its R-(-) enantiomer levoprotiline is totally devoid of this property. Oxaprotiline significantly resembled amitriptyline in its antidepressant potential. Conversely, levoprotiline significantly resembled placebo in antidepressant potential. Therefore, NA uptake was necessary for the observed therapeutic effect of this experimental antidepressant.

The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II.

The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.

Prevention of nitrate tolerance with angiotension converting enzyme inhibitors.

BACKGROUND: Activation of neurohumoral hormones or sulfhydryl group depletion may contribute to the development of nitroglycerin tolerance. In an attempt to prevent nitrate tolerance, this study evaluated the interaction of nitroglycerin with angiotensin converting enzyme (ACE) inhibitors with and without a sulfhydryl group. METHODS AND RESULTS: Thirty-four subjects were randomized to a 7-day regimen of enalapril 10 mg b.i.d., captopril 25 mg t.i.d., or placebo. Venodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in venous volume after administration of 0.4 mg sublingual nitroglycerin. Plethysmographic measurements were obtained serially 1) at baseline, 2) after 4 days of ACE inhibitor or placebo, 3) 2 hours after application of a 10 mg/24 hr nitroglycerin patch, and 4) 74 hours after continuous nitropatch application. ACE inhibition alone caused no significant change in the response to sublingual nitroglycerin. Nitrate response remained unchanged after 2 hours ("acute") of nitropatch exposure in all three groups. After 74 hours ("chronic") of continuous nitropatch application, the venodilator response to sublingual nitroglycerin was reduced by 40% in the placebo group, 10% in the enalapril group, and 2% in the captopril group. This attenuation was significant only in the placebo group (p less than 0.01). Pairwise comparison of nitrate response between groups was significantly different between the captopril and placebo groups (p less than 0.01) and between the placebo and enalapril groups (p less than 0.05). Plasma renin levels increased equally in the enalapril and captopril groups. Body weight increased only in the placebo group, suggesting prevention of nitrate-induced volume expansion in the ACE inhibitor groups. CONCLUSIONS: This study demonstrates that ACE inhibitors may prevent nitrate tolerance to long-term nitrate therapy.

Methionine restores the venodilative response to nitroglycerin after the development of tolerance.

Depletion of sulfhydryl groups may contribute to nitroglycerin tolerance after long-term exposure. This study was performed to assess whether methionine, an amino acid capable of augmenting sulfhydryl availability, would restore the venodilative response to sublingual nitroglycerin once tolerance had developed. The venodilative response to organic nitrates was assessed with use of the equilibration technique of forearm plethysmography. Venous volume was measured before and after sublingual administration of 0.4 mg of nitroglycerin at baseline study and after 5 g of intravenous methionine. Retesting was performed 2 h after application of a 10 mg nitroglycerin patch and compared with the response after 74 h of nitroglycerin patch exposure before and after intravenous methionine. Methionine alone had no intrinsic venodilative action. Although the venous volume at rest was unchanged after methionine administration, the response to sublingual nitroglycerin was potentiated compared with baseline values (37 +/- 15% versus 32 +/- 13%, p less than 0.02). During nitroglycerin patch exposure, the response to sublingual nitroglycerin was significantly attenuated at 74 h compared with the response at 2 h of exposure (16 +/- 10% versus 31 +/- 13%, p less than 0.001). The venodilative response to sublingual nitroglycerin was restored at 74 h after methionine administration (35 +/- 14% versus 16 +/- 10%, p less than 0.001). Thus, methionine potentiates the venodilative effect of sublingual nitroglycerin both immediately and in the setting of nitrate tolerance.

Neurobiology of obsessive compulsive disorder--a serotonergic basis of Freudian repression.

Intrusive thoughts and images, often of a violent, horrific, or blasphemous nature are the hallmark of Obsessive Compulsive Disorder (OCD). OCD patients frequently also often have reductions in normal serotonergic (5-HT) function. This paper proposes a model of 5-HT function involving the routine filtering and suppression of violent or libidinal impulses. This model accounts for OCD as an instance of failed inhibition. The model also appears to resemble Freud's model of ego-id interactions at least in part, suggesting that it may be possible to psychobiologically substantiate a Freudian metaphor.