Leon Grunhaus

Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin.

We have previously shown that a number of depressed patients demonstrated a failure to suppress corticotrophic secretion, as measured by beta-Endorphin/beta-Lipotropin (beta-End/beta-LPH levels), following dexamethasone challenge. The current study is an extension and replication of these findings, as well as an analysis of some of the biological variables which may contribute to the variance in beta-End/beta-LPH nonsuppression. We continue to observe a high rate of beta-End/beta-LPH nonsuppression in depressed patients following dexamethasone; this escape at the pituitary level is even observed in a number of patients who demonstrate normal cortisol suppression. Advancing age, particularly in women, led to higher baseline cortisol, lower baseline beta-End/beta-LPH, and a greater likelihood of being a nonsuppressor on one or both measures.

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.

Clinical correlates of sleep onset rem periods in depression

in euthymic patients with primary affective illness. Science 208:200. Sitaram N, Gillin JC, Bunney WE Jr (1984): Cholinergic and catecholaminergic receptor sensitivity in affective illness: Strategy and theory. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins, p 629. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders, 3rd ed. New York: New York State Psychiatric Institute. Zandberg P, DeJong W (1977): Localization of catecholaminergic receptor sites in the nucleus tractus solitarii involved in the regulation of arterial blood pressure. Prog Brain Res 47: 117.

Major depressive disorder and panic disorder. Effects of comorbidity on treatment outcome with antidepressant medications

Recent studies suggest that major depressive disorder (MDD) and panic disorder (PD) may coexist in a significant number of patients. The relevance of this association may be such that patients with the simultaneous diagnosis are at risk for more severe psychopathology and poorer treatment outcome. To explore this possibility further, we compared treatment outcome of two groups of patients: one with comorbidity of MDD and PD (N = 19) and another with MDD only (N = 22). Patients with comorbidity of MDD and PD scored significantly worse on a number of outcome assessments.

Effects of yohimbine on cerebral blood flow, symptoms, and physiological functions in humans

Objective Increases in adrenergic activity are associated with stress, anxiety, and other psychiatric, neurological, and medical disorders. To improve understanding of normal CNS adrenergic function, CBF responses to adrenergic stimulation were determined. Methods Using PET, the CBF changes after intravenous yohimbine, an &agr;2-adrenoreceptor antagonist that produces adrenergic activation, were compared with placebo in nine healthy humans. Heart rate, blood pressure, Paco2, plasma catecholamines, and symptom responses were also determined. Results Among nonscan variables, yohimbine produced significant symptom increases (including a panic attack in one subject), a decrease in Paco2 due to hyperventilation, increases in systolic and diastolic blood pressure, and a trend toward a significant norepinephrine increase. Among scan results, yohimbine produced a significant decrease in whole-brain absolute CBF; regional decreases were greatest in cortical areas. Medial frontal cortex, thalamus, insular cortex, and cerebellum showed significant increases after normalization to whole brain. Medial frontal CBF change was correlated with increases in anxiety. A panic attack produced an increase instead of a decrease in whole-brain CBF. Factors potentially contributing to the observed CBF changes were critically reviewed. Specific regional increases were most likely due in large part to activation produced by adrenergically induced anxiety and visceral symptoms. Conclusions This study supports the relationship of anxiety and interoceptive processes with medial frontal, insular, and thalamic activation and provides a baseline for comparison of normal yohimbine-induced CNS adrenergic activation, adrenergically-based symptoms, and other markers of adrenergic function to stress, emotion, and the adrenergic pathophysiologies of various CNS-related disorders.

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.

Yohimbine bioavailability in humans.

SummaryPharmacokinetic profiles were determined in seven healthy young male subjects following single oral and intravenous doses of 10 mg of yohimbine hydrochloride.The drug was rapidly eliminated (t1/2β 0.58 h orally and t1/2β 0.68 h intravenously). Following intravenous administration the data fit a two-compartment pharmacokinetic model, with a very rapid distribution phase (t1/2a was approximately 6 min). Both the oral and the intravenous yohimbine clearance values were high but oral clearance values were much higher (mean 9.77 ml·min−1·kg−1 intravenous versus 55.9 ml·min−1·kg−1 oral). The oral bioavailability showed great variability, ranging from 7% to 87% (mean value was 33%).The imcomplete oral bioavailability of yohimbine may reflect either incomplete absorption from the gastrointestinal tract or an hepatic first pass effect. Although yohimbine is rapidly absorbed when given orally, the bioavailability is quite variable and considerable individualization of dosing may be necessary when the drug is used orally for clinical indications.

Age effects in serial hypothalamic - pituitary - adrenal monitoring

To evaluate age effects on hypothalamic-pituitary-adrenal (HPA) regulation in depressives, we studied 65 patients with major depressive disorder, endogenous subtype. With each patient serving as his or her own control, we compared weekly dexamethasone suppression test (DST) results among three age subgroups (less than 40 years, n = 18; 40-70 years, n = 40; greater than 70 years, n = 7). The oldest patient group had higher mean post-dexamethasone plasma cortisol concentrations both before and after treatment, and more were DST nonsuppressors. Life table analyses revealed that elderly patients who were DST nonsuppressors had significantly slower patterns of normalization during treatment and that fewer elderly patients ever achieved normal suppression. The results indicate that age effects on HPA function may be confounded with other aspects of depression, such as severity, chronicity and number of previous episodes.

Panic Attacks: A Review of Treatments and Pathogenesis

In the psychiatric literature, panic attacks have been considered as part of the clinical manifestations of anxiety neurosis, agoraphobia, functional cardiovascular disturbances, and the phobic depersonalization syndrome. Even though recurrent spontaneous panic attacks are described in these entities, the importance ascribed to them has been a minor one. Therefore, panic attacks are poorly understood from a psycho-physio-pathological point of view. In the past years, new trends in the nosology of psychiatric disorders have grouped the recurrent spontaneous panic attacks under the heading “panic disorder and agoraphobia with panic attacks.” In this view, we present the results of the controlled pharmacological trials on patients complaining of panic attacks. Some relationships between panic attacks, panic disorder, and agoraphobia are discussed.

Severity of depression and hypothalamic‐pituitary‐adrenal axis dysregulation: identification of contributing factors

Severity of depression, as reflected by total scores on depression rating scales, has been established as one of several major sources of variance associated with hypothalamic‐pituitary‐adrenal axis dysregulation in patients with major depressive disorder. To determine which of the symptoms comprising clinically defined severity of illness contribute most to this relationship, we studied the associations between postdexamethasone plasma cortisol levels and components of the Hamilton Rating Scale for Depression (HRSD) in 114 patients with major depressive disorder. At pretreatment baseline, severity of depression was modestly but significantly correlated with postdexamethasone plasma cortisol; a large part of this relationship was associated with the anxiety components of the HRSD. When relationships between postdexamethasone plasma cortisol and severity measures were studied longitudinally during treatment, this contribution of the anxiety items persisted. The anxiety associated with depression appears to be a major clinical factor associated with the hypothalamic‐pituitary‐adrenal axis dysregulation in major depressive disorder.;