Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.

BACKGROUND: Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established. AIM: To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication. METHODS: Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher's exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1-18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate. CONCLUSION: This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.

Cortisol secretion in endogenous depression. I. Basal plasma levels.

Plasma levels of cortisol were sampled for 24 hours in 32 endogenously depressed (ED) patients and 72 normal controls who also underwent the dexamethasone suppression test. The ED patients had significantly higher mean 24-hour plasma levels of cortisol (means 24h PC). However, means 24h PC values of subjects in both groups were normally distributed, with a marked overlap between the two. Only seven ED patients had means 24h PC values higher than 2 SDs from the normal mean (greater than 10 micrograms/dL). An abnormal dexamethasone suppression test result was only partially related to basal cortisol levels. The mean plasma level of cortisol between 1 and 4 PM was found to be highly correlated with the means 24h PC value in ED patients, as has been previously reported in normal subjects and patients with various other diseases (in which it also powerfully discriminated between hypersecretors and normosecretors). This finding supports the use of mean cortisol levels between 1 and 4 PM as a reliable and convenient indication of cortisol secretion.

Cortisol secretion in endogenous depression. II. Time-related functions.

Plasma levels of cortisol were sampled for 24 hours in 32 endogenously depressed (ED) patients and 72 controls to examine mean 24-hour plasma levels of cortisol, intervention in the feedback mechanism of the hypothalamic-pituitary-adrenal system (the dexamethasone suppression test), the circadian rhythm of cortisol secretion and its magnitude, and the ultradian rhythm of cortisol secretion. The main difference in the pattern of cortisol secretion in ED patients, as compared with controls, was in the ultradian rhythm. No acrophase or nadir advance of cortisol secretion in endogenous depression was found when age was controlled, but there was an earlier timing of first secretory episode of cortisol (during night). Only some ED patients have abnormalities in each of the functions studied, and they only partially overlap each other. The results suggest that abnormal cortisol secretion in depression should not be viewed as a monolithic malfunction characteristic of endogenous depression.

Paradoxical cortisol responses to dextroamphetamine in endogenous depression.

Dextroamphetamine hydrochloride was administered intravenously (IV) in the morning and evening to 22 unmedicated patients with severe endogenous depressions and 18 normal control subjects. While the normal subjects generally had a sharp increase in plasma cortisol level by 30 minutes after drug administration, two thirds of the depressed patients showed instead a paradoxical suppression of cortisol levels by 60 minutes. Discrimination between normal subjects and depressives was greatest in the evening. These results are consistent with other reports of abnormal cortisol responses in depressed patients to smaller IV doses of dextroamphetamine and larger doses of methamphetamine hydrochloride. A defect in activation or noradrenergic alpha receptors may account, in part, for the abnormal cortisol responses. The dextroamphetamine cortisol test in other patient populations requires study before its diagnostic use in endogenous depression can be established.

Growth hormone response to dextroamphetamine in depressed patients and normal subjects.

The human growth hormone (HGH) response to dextroamphetamine sulfate (doses, 0.1 and 0.15 mg/kg) was determined in both the morning and evening in patients with endogenous and atypical depression and in normal young men and normal postmenopausal women. Although the HGH response was found to be reduced in endogenously depressed postmenopausal women, it was equally reduced in normal postmenopausal women and in patients with atypical depression. Depressed and normal men had larger HGH responses, but there were no differences between depressed and normal men. These results do not confirm an earlier report that the reduced HGH response to dextroamphetamine is specific to endogenous depression. The results do suggest the importance to control for other variables in studies of HGH responses in psychiatric patients.

Afternoon continuous plasma levels of 3-methoxy-4-hydroxyphenylglycol and age. Distinctive biologic subgroups of endogenous depression?

Afternoon continuous plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were first shown to be a good representation of the mean 24-hour plasma level of MHPG in 18 normal subjects. Then, after the stability of the procedure was tested and retested, the afternoon continuous test for plasma MHPG levels was performed in 57 normal subjects and 42 endogenously depressed patients. A significant correlation between plasma MHPG levels and age was found in normal subjects and depressive patients. When the variable of age was taken into account, a distinct pattern of increasing plasma MHPG levels with age--the "MHPG per age"--was found in the depressed patients, especially the women, who could be divided into high or low MHPG per age groups. There was almost no association between plasma levels of MHPG or MHPG per age values and clinical symptoms, and the two biologic subgroups did not differ clinically.

Failure of dopaminergic blockade to affect prolactin, growth hormone, and cortisol responses to insulin-induced hypoglycemia in schizophrenics.

The PRL, GH, and cortisol responses to insulin tolerance tests (ITTs) were evaluated in 12 medically healthy schizophrenic patients during a drug-free period and after 1 and 6 weeks of treatment with penfluridol, a potent, long acting, dopamine-blocking neuroleptic. Hypoglycemic responses were the same before and during penfluridol therapy. Although resting PRL levels were evaluated during initial penfluridol therapy (week 1), hypoglycemia provoked a further substantial PRL increment, not significantly different in magnitude from that induced by hypoglycemia during the drug-free period. However, there was a 54% reduction (P less than 0.05) in the increase in the area under the PRL curve during week 6 compared to the drug-free period. Regarding GH and cortisol, resting levels, areas under the curve, and maximal increments after ITT were essentially the same during weeks 1 and 6 of penfluridol treatment as in the drug-free period. The failure of 1 week of dopaminergic blockade to significantly alter the hormonal (PRL, GH, and cortisol) responses to ITT in the group as a whole suggests that dopamine-blocking mechanisms play little role in mediating these responses, at least in schizophrenic patients.

Depression, natural killer cell activity, and cortisol secretion.

Natural killer (NK) cell activity was evaluated in 34 ambulatory patients with Major Depressive Disorder (MDD) and 21 healthy controls. No mean differences between the groups were found. However, female depressives (n = 19) exhibited higher NK activity than female controls (n = 14). The relationship between cortisol secretion and NK activity was examined using an integrated cortisol value derived from multiple blood samples taken between 1:00 and 4:00 PM. This comprehensive assessment of cortisol secretion circumvents spurious "single stick" cortisol values and provides a more accurate determination of hypercortisolemia than the dexamethasone suppression test. NK activity in depressives with cortisol hypersecretion (greater than 11 micrograms/dl) (n = 7) was no different than NK activity in depressives and controls with normal cortisol secretion. Furthermore, there was no correlation between cortisol secretion and NK activity in any of the groups. These results indicate that decreased NK activity is not a consistent finding in MDD and cannot be predicted by the presence of hypercortisolemia in these patients.

Therapeutic indications for serotonin-potentiating compounds: a hypothesis.

The original antidepressants, tricyclics and MAO inhibitors, increase the availability in the brain of both 5-HT and NA. Prompted by clinical findings suggestive of 5-HT disturbances in depression, drugs were developed that increase 5-HT selectively. Data are presented that suggest that broad-spectrum compounds may provide better conditions for antidepressant effects than the 5-HT-selective ones. The hypothesis is proposed that 5-HT potentiators are partial antidepressants, in that they predominantly reduce the anxiety/aggressive component of the depressive syndrome, and deserve to be tested in conditions with heightened anxiety and/or aggression irrespective of the nosological diagnosis. Tentative evidence relates diminished 5-HT metabolism to disordered impulse control. Based on these data, trials of 5-HT potentiators in impulse control disorders unrelated to aggressive drives seem warranted.

The MCPP challenge test in schizophrenia: hormonal and behavioral responses.

In a neuroendocrine challenge paradigm, the present study investigated responses of schizophrenic patients to m-chlorophenylpiperazine (MCPP), a serotonin (5-hydroxytryptamine, 5HT) agonist. In an oral dose of 0.25 mg/kg, MCPP was administered in a placebo-controlled double-blind design to male schizophrenic patients (n = 7) and normal male controls (n = 8). Behavioral (Positive and Negative Syndrome Scale; PANSS) and hormonal (cortisol, prolactin) variables were measured over the subsequent 210 min. The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p less than 0.05), with specific worsening of PANSS-positive symptoms (p less than 0.025) and PANSS activation (p less than 0.001). In addition, the schizophrenic patients showed significantly lower cortisol (p less than 0.05) and prolactin (p less than 0.05) responses than the normal subjects. The schizophrenic patients had lower peak MCPP blood levels than the normal subjects, although this difference was not statistically significant. The findings are discussed in terms of 5HT receptor(s) sensitivity and the pharmacokinetics of MCPP in schizophrenia.

Alprazolam blockade of CO2-provoked panic in patients with panic disorder.

The primary aim of this study was to determine if pretreatment with a single dose of alprazolam reduces anxiety and panic provoked by the inhalation of 35% carbon dioxide (CO2) in patients with panic disorder. Ten panic disorder patients participated in a CO2 challenge test after pretreatment with a single dose of alprazolam (1 mg p.o.) or placebo in a randomized, double-blind, within-subjects design. Seventy percent of the subjects had a panic attack with placebo, compared to only 10% with alprazolam. Alprazolam reduced the number and severity of panic symptoms and baseline anxiety significantly more than placebo. This study demonstrates the efficacy of the acute administration of alprazolam to block panic attacks and supports the usefulness of the CO2 challenge as an analogue method to study panic disorder.

ECT in metropolitan New York hospitals: a survey of practice, 1975-1976.

Of New York psychiatric facilities surveyed, 83% used ECT. Five percent of patients in university and private nonprofit hospitals, less than 1% in public hospitals, and 21% in private for-profit hospitals received ECT. Practices and procedures were remarkably uniform, except that less than 17% of units used unilateral ECT. Training programs were minimal and unplanned. Differences in incidence of use result from staff training, public antipathy, and economic factors.

Atypical depression: clinical aspects and noradrenergic function.

OBJECTIVE: The authors assessed the frequency of atypical depression in depressed outpatients and compared clinical and biological features of patients with atypical and nonatypical depression. METHOD: Depressed outpatients (N = 114) were diagnosed with the Schedule for Affective Disorders and Schizophrenia (SADS) according to Research Diagnostic Criteria. Patients were assessed for presence or absence of atypical depression with the Atypical Depressive Disorder Scale. Atypical depression was defined as the presence of mood reactivity during the depressive episode, along with at least one of four associated features: hypersomnia, hyperphagia, leaden paralysis, and rejection sensitivity. All patients completed the SCL-90 and were rated with the Hamilton Depression Rating Scale, extracted from the SADS. To assess biological functioning, the authors examined cortisol response to 75 mg of desipramine, a relatively selective norepinephrine reuptake inhibitor. RESULTS: Twenty-nine percent of patients met criteria for atypical depression. Patients with atypical depression were significantly more likely to be female. Patients with atypical and nonatypical depression did not differ on SCL-90 subscale scores. Although extracted Hamilton depression scale scores were significantly higher for patients with nonatypical depression, the difference was not clinically significant. Patients with atypical depression exhibited a significantly different cortisol response to desipramine injection than patients with nonatypical depression, which suggested that nonatypical depression may be associated with a more impaired norepinephrine system. CONCLUSIONS: In view of data in this study, as well as earlier studies, atypical depression has a unique symptom profile, may be widely prevalent, has a distinct treatment response, and may indicate a less impaired biological system than nonatypical depression. Since this is the first report to evaluate the frequency of atypical depression as well as the norepinephrine system in atypical depression, this study needs to be replicated. Nonetheless, the data support the inclusion of atypical depression as a subtype of the depressive disorders in DSM-IV.

Prevalence of specific suicidal behaviors in a high school sample.

Of 380 high school students who completed an anonymous survey concerned with their experience with suicidal behavior, 60% reported that they had thought about killing themselves. These thoughts varied with respect to persistence and planfulness. Almost 9% reported that they had actually made at least one attempt to kill themselves and over half of the suicide attempters reported at least two attempts. Fewer than half of the attempters reached the attention of mental health professionals. The data on family history of suicidal behavior suggest that the suicidal ideators and the suicide attempters represent overlapping groups.

A survey of tardive dyskinesia in psychiatric outpatients.

The authors found a high prevalence--43.4% of tardive dyskinesia in a sample of psychiatric outpatients, a population previously thought to be at nominal risk for development of this syndrome. There was no significant relationship between the presence of dyskinesia and age, sex, years of neuroleptic use, or various organic factors. The effects of dentures and of drug combinations are discussed, and it is noted that structured scales of dyskinesia and videotope recordings are important tools in diagnosing and following the course of dyskinesia.

Cortisol secretion and dexamethasone response in depression.

The authors administered 2 mg of dexamethasone at 11:00 p.m. to 37 unmedicated hospitalized endogenously depressed patients and assessed their plasma cortisol response at 4:00 and 11:00 p.m. the next day. In addition, on nondexamethasone days 26 of these patients had mean 24-hour plasma cortisol concentration determinations from samples taken at 30-min intervals and 32 had plasma determinations from a single sample taken at 4:00 and 11:00 p.m. Mean 24-hour plasma cortisol concentration was elevated in 50%; only 7 of the 26 were dexamethasone resistant, and 6 of these 7 were hypersecretors. The authors suggest that dexamethasone resistance reflects the abnormality of cortisol hypersecretion in depression and that the 2-mg dexamethasone suppression test is a highly specific but not very sensitive indicator of hypersecretion.

The normalcy of self-proclaimed "normal volunteers".

Volunteers who claimed they were "healthy and normal" and did not reveal any physical or mental abnormality or medication use during brief structured interviews underwent detailed structured interviews with the Schedule for Affective Disorders and Schizophrenia. Diagnoses were based on the Research Diagnostic Criteria (RDC), and family history was determined with the Family History RDC. Of the 121 volunteers, 16.5% met criteria for diagnoses of current mental disorders. Of the 104 without current DSM-III axis I diagnoses, 35.6% had past histories and 39.4% had family histories of mental illness. These results emphasize the need for thorough assessment of "normal volunteers."

High cholesterol levels in patients with panic disorder.

OBJECTIVE: This study was undertaken to help clarify whether the higher cholesterol levels found in patients with panic disorder are a complication of panic disorder only or are associated with any psychiatric disorder. METHOD: The subjects of the study were 30 patients with panic disorder and 30 patients with major depression, diagnosed according to the Structured Interview for DSM-III-R, and 30 normal control subjects. The three groups were matched for sex and age, and none of the subjects had alcohol/drug abuse, abnormal ECGs, or unstable medical conditions. Blood samples were drawn at random times, and serum cholesterol levels were determined. RESULTS: The patients with panic disorder had significantly higher serum cholesterol levels than did the patients with major depression and the normal control subjects. Among the patients with major depression, histories (current or past) of anxiety disorders were associated with significant elevation of serum cholesterol levels. The presence of stable medical conditions was not associated with higher cholesterol levels in any of the three groups of subjects. CONCLUSIONS: Higher cholesterol levels were particularly associated with panic disorder in comparison with major depression. Higher levels of cholesterol in panic disorder are hypothesized to be a result of increased noradrenergic activity, which may be the underlying biological/neurochemical mechanism for symptoms of panic disorder, including anticipatory anxiety.

Suicidal behaviors in adult psychiatric outpatients, I: Description and prevalence.

OBJECTIVE: Because the findings of previous studies of suicidal behaviors in psychiatric outpatients may not necessarily generalize to outpatients with a wide spectrum of psychiatric diagnoses, the authors evaluated the prevalence of suicidal behaviors in a large general psychiatric outpatient clinic whose patients represented a full spectrum of psychiatric illness. METHOD: A total of 651 patients participated in the study between 1987 and 1989. These patients had sought treatment at the outpatient psychiatry department of a private nonprofit hospital. Before being interviewed for treatment, all patients were given a comprehensive self-rating survey packet that included the Harkavy Asnis Suicide Survey and the Hopkins Symptom Checklist-90. The Harkavy Asnis Suicide Survey is a self-report questionnaire that assesses demographic variables, current and past history of suicidal behaviors of the patient as well as family members and peers, and a detailed description of each previous attempt. RESULTS: Fifty-five percent of the patients had a history of suicidal ideation, and 25% reported at least one previous suicide attempt. Approximately half of the suicide attempters reported multiple attempts. The predominant methods of attempt were overdose (53%), jumping (17%), and wrist cutting (17%). Suicidal behavior was prevalent in most diagnostic groups. The rates of suicidal ideation among patients with mood disorders (major depression, dysthymia, and bipolar disorder), adjustment disorders, and alcohol/substance abuse were significantly greater than that of the patients with generalized anxiety disorder. CONCLUSIONS: The authors conclude that suicidal behavior is prevalent among patients who seek treatment in a general outpatient department.

Plasma cortisol secretion and REM period latency in adult endogenous depression.

The authors studied the relationship of plasma cortisol secretion and REM period latency in 25 patients with endogenous depression. The 8 patients (32%) with cortisol hypersecretion had a significantly shortened REM period latency in comparison with the 17 with normal cortisol secretion. Furthermore, an extremely short REM latency (20 minutes or less) occurred almost exclusively in those with cortisol hypersecretion. The authors discuss possible neurotransmitter disturbances responsible for these abnormalities and the clinical implications of these findings.