Is late-onset schizophrenia a subtype of schizophrenia?

OBJECTIVE: To determine whether late-onset schizophrenia (LOS, onset after age 40) should be considered a distinct subtype of schizophrenia. METHOD: Participants included 359 normal comparison subjects (NCs) and 854 schizophrenia out-patients age >40 (110 LOS, 744 early-onset schizophrenia or EOS). Assessments included standardized measures of psychopathology, neurocognition, and functioning. RESULTS: Early-onset schizophrenia and LOS groups differed from NCs on all measures of psychopathology and functioning, and most cognitive tests. Early-onset schizophrenia and LOS groups had similar education, severity of depressive, negative, and deficit symptoms, crystallized knowledge, and auditory working memory, but LOS patients included more women and married individuals, had less severe positive symptoms and general psychopathology, and better processing speed, abstraction, verbal memory, and everyday functioning, and were on lower antipsychotic doses. Most EOS-LOS differences remained significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness. CONCLUSION: Late-onset schizophrenia should be considered a subtype of schizophrenia.

The cholinergic rapid eye movement induction test with arecoline in depression.

The cholinergic rapid eye movement (REM) induction test using arecoline hydrobromide, a cholinergic muscarinic receptor agonist, was studied in patients with affective disorder and in normal controls to determine whether or not depression is associated with enhanced induction of REM sleep by muscarinic agonists. Arecoline induced REM sleep in a dose-dependent fashion in both patients and controls compared with placebo infusions. Compared with normal controls, patients entered REM sleep significantly more rapidly following intravenous administration of 1.0 mg of arecoline hydrobromide than they did following administration of 0.5 mg of arecoline hydrobromide or placebo. These results, as well as those of previous studies, support the hypothesis that patients with affective disorder show a functional supersensitive induction of REM sleep in response to muscarinic receptor agonists and may be consistent with the hypothesis that functional muscarinic receptor "up regulation" is associated with depression.

The effects of lisuride on mood and sleep during acute withdrawal in stimulant abusers: a preliminary report.

Psychostimulant abusers often experience anhedonia, depression, fatigue, craving, and hypersomnia and increased propensity for rapid eye movement (REM) sleep during periods of acute and subacute withdrawal from cocaine and amphetamine. These signs and symptoms may reflect a state of relative functional dopamine depletion in the brain during abstinence. Lisuride, which has dopaminergic agonist effects, has been reported to reduce signs of psychostimulant withdrawal in rodent models of stimulant abuse. These observations prompted us to test the effects of oral administration of lisuride for 3 weeks (up to 4.0 mg daily) on mood and craving ratings in a double-blind, parallel design, controlled study in hospitalized stimulant abusers during acute withdrawal from cocaine or amphetamine. Although administration of lisuride significantly prolonged REM latency and reduced REM time, amelioration of other signs of withdrawal was not significantly greater in lisuride as compared with placebo treated patients. Self-rated craving ratings, however, were low in both groups throughout the hospital stay. Further studies, perhaps in patients with more severe symptoms during withdrawal, are needed to fully test the efficacy of lisuride in the treatment of stimulant withdrawal.

Neuroendocrine effects of ovine corticotropin-releasing hormone in panic disorder patients.

A number of neuroendocrine abnormalities have been reported in panic disorder patients: the most extensively studied being disturbances of hypothalamic-pituitary-adrenal function (Curtis et al. 1982; Leiberman et al. 1983; Uhde et al. 1988). The recent sequencing and synthesis of corticotropin-releasing hormone now allows direct testing of pituitary responsivity to this neuropeptide in affective and panic disorder patients (Holsboer et al. 1984; Gold et al. 1986; Roy-Byrne et al. 1986; Holsboer et al. 1987; Risch et al. 1988). We report the effects of intravenously administered ovine corticotropin-releasing hormone (0.03 micrograms/kg) on plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol in a small group of panic disorder patients and age- and sex-matched normal controls.

Polygraphic sleep measures differentiate alcoholics and stimulant abusers during short-term abstinence.

We hypothesized that stimulant abusers would sleep more and have more rapid eye movement (REM) sleep than primary alcoholics during acute withdrawal (first 10 days drug free) but would have opposite patterns during subacute withdrawal (days 11-14 drug free). We compared polygraphic sleep patterns during acute withdrawal (days 3-10) for 7 stimulant abusers and 8 alcoholics and during subacute withdrawal (days 11-14) for 7 different stimulant abusers and 8 different alcoholics. For comparison purposes, a group of normal controls from our preexisting database were matched for age and gender. Two statistically significant interactions were found: consistent with our hypothesis, stimulant abusers showed greater total sleep (TST) and REM sleep during acute withdrawal than subacute withdrawal, compared with alcoholics. In contrast, alcoholics showed less TST and REM sleep during acute withdrawal than during subacute withdrawal. Our polygraphic sleep data support the hypothesis that physiological withdrawal differs in alcoholics compared with stimulant abusers. Different mechanisms may underlie withdrawal in these two substances.

Dose dependent inhibition of REM sleep in normal volunteers by biperiden, a muscarinic antagonist.

We tested the effect of biperiden (2, 4, and 8 mg per os 30 min before bedtime) on the polygraphically recorded sleep of normal volunteers (n = 8). Biperiden is a cholinergic, muscarinic receptor antagonist that may preferentially block the M1 receptor subtype. Compared with placebo, biperiden significantly prolonged rapid eye movement (REM) latency and suppressed REM sleep time and REM percentage in a dose-dependent manner. These REM suppressing effects of biperiden are similar to those previously reported with scopolamine and other nonselective muscarinic receptor antagonists. Because of uncertainties about the pharmacological specificity of biperiden, further studies are needed to determine the mechanism of action and the role of M1 receptors subtypes in the regulation of REM sleep.

The effects of physostigmine infusion on patients with panic disorder.

Nine patients who met both DSM-III and RDC criteria for panic disorder and nine age-matched normal controls received infusions of physostigmine. The patients and normal controls did not differ in either their self-reported or the observer-reported ratings of anxiety, mood, or activation. The two subject groups also did not differ in blood pressure, pulse, or cortisol responses to physostigmine. Physostigmine did not provoke panic attacks in either the control or patients groups.

The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group.

In order to determine the effect of an anticholinergic agent on mood and sleep, scopolamine (0.4 mg IM) was administered before bedtime for three consecutive nights to 10 depressed patients (8 with a history of alcohol abuse) and 10 normal comparison subjects. The patients had a small, statistically significant antidepressant response on the second morning of treatment. Scopolamine inhibited rapid eye movement (REM) sleep and prolonged REM latency equally in depressed patients and the normal comparison group. Partial tolerance to the REM inhibiting effect of scopolamine developed between the first and third night of treatment. A REM rebound occurred during recovery nights. These results are consistent with concepts relating central cholinergic mechanisms to the control of REM sleep. Compared with controls, patients showed a greater increase in Stage 2 and Stage 2% and a lesser and increase in Delta (Stage 3 and 4) sleep % and Stage 4% on the first night of treatment. Further, well-controlled studies are needed to determine whether anticholinergic drugs possess clinically significant antidepressant effects.

The cholinergic REM sleep induction test with pilocarpine in mildly depressed patients and normal controls.

Previous studies suggested that depressed patients enter rapid-eye movement (REM) sleep more quickly than normal controls following the administration of muscarinic agonists such as arecoline or RS 86. We recently reported that pilocarpine, an orally active muscarinic agonist, induced REM sleep and reduced Stage 3 & 4 (Delta) sleep in young normal volunteers. In this study we present preliminary evidence that pilocarpine had similar effects on REM latency, REM percentage, and Delta (Stages 3 & 4) sleep percentage in depressed patients and controls. Pilocarpine, however, decreased stage-4 sleep in controls more than in depressed patients. Because this group of patients were only mildly depressed at the time of the study, had a high frequency of comorbid substance abuse diagnoses, and had normal electroencephalogram (EEG) sleep patterns under placebo conditions, further studies are necessary to test the hypothesis that depressed patients show hypersensitive cholinergic REM sleep induction.

Mitogen-stimulated lymphocyte proliferation and pituitary hormones in major depression.

To assess cellular immune status and the hypothalamic-pituitary (HP) axis in patients with major depression, we examined peripheral blood mononuclear cells (PBMC) and measured the plasma levels of cortisol, adrenocorticotropin hormone (ACTH), growth hormone (GH), and prolactin (PRL). Twenty patients with major depression were compared with 20 control subjects matched for age, sex, and race. The dose-response curves for concanavalin-A (Con-A) and phytohemagglutinin (PHA) stimulation were not significantly different between the two groups. The patients had decreased Con-A-stimulated T-lymphocyte proliferation when compared to the control subjects, but only at the lowest suboptimal concentration of Con-A. None of the four concentrations of PHA-stimulated proliferation were different between the two groups, neither was PHA-induced interleukin-2 production. Within the patient group only, plasma prolactin (PRL) correlated significantly with stimulated lymphocyte proliferation using two optimal concentrations of PHA and one optimal concentration of Con-A, when the proliferation was expressed using the stimulation index.

Increased REM sleep density at admission predicts relapse by three months in primary alcoholics with a lifetime diagnosis of secondary depression.

BACKGROUND: Having previously reported that 3-month relapse was associated with increased admission REM pressure in nondepressed primary alcoholics, we hypothesized that baseline polysomnography would predict outcome in primary alcoholics with a lifetime diagnosis of secondary depression. METHODS: Twenty-one primary alcoholics with secondary depression received polysomnography and the Hamilton Depression Rating Scale during the first and fourth weeks of a 1-month inpatient alcohol treatment program. Exclusion criteria included serious illness, current major alcohol withdrawal symptoms, other Axis I diagnoses, sleep apnea, nocturnal myoclonus, and psychoactive substances within 14 days of polysomnography. Relapse was defined as drinking any alcohol between hospital discharge and 3-month follow-up. RESULTS: Relapsers' total sleep time was reduced, and REM density (reflecting REM sleep ocular activity) was increased significantly throughout admission compared with abstainers. Sleep continuity and Hamilton scores improved by discharge in sober and relapsing alcoholics. Factors derived from admission REM latency, REM percent, and REM density predicted sobriety vs. relapse within 3 months after hospital discharge in 76% of patients. Admission REM density was greater, and total sleep time was less in relapsers than in patients sober at 3 months. CONCLUSIONS: Results suggest that increased REM density and decreased total sleep time at about 2-4 weeks of abstinence predict relapse by 3 months in depressed alcoholics.

Effects of a tryptophan-free amino acid drink challenge on normal human sleep electroencephalogram and mood.

BACKGROUND: Serotonin has been implicated in the regulation of sleep and mood. In animals a tryptophan-free amino acid drink (TFD) challenge has been found to reduce brain serotonin. We hypothesized this TFD would produce alterations in electroencephalographic (EEG) sleep commonly associated with depression, i.e. an enhancement of rapid eye movement (REM) sleep, and adversely affect mood ratings in humans. METHODS: We investigated the effects of a TFD challenge in 11 healthy male subjects on EEG sleep and mood (assessed by Profile of Mood States). All subjects received on separate occasions an experimental drink containing approximately 100 g of an amino acid mixture (100% TFD) and a control drink containing one fourth strength (25% TFD) of the experimental drink 5 hours prior to sleep (6:00 PM). RESULTS: Both drinks significantly decreased plasma tryptophan levels 5 hours postchallenge (11:00 PM). Both drinks significantly decreased REM latency, and the 25% TFD also increased REM time and REM% compared to baseline. No significant changes were found in subjective ratings of depression; however, subjects reported confusion and tension and a decrease in elation, vigor, and friendliness compared with baseline. CONCLUSIONS: These TFD findings further support the involvement of serotonin deficiency in EEG sleep findings commonly seen in depression.

A critical appraisal of mitogen-induced lymphocyte proliferation in depressed patients.

OBJECTIVE: The authors' goal was to evaluate the utility of mitogen-induced lymphocyte proliferation assays in clinical research in psychoimmunology. METHOD: They examined 23 depressed patients and 23 matched comparison subjects with this assay. There were no significant differences between these groups. They then combined the results of this study with the results of their previous study of 20 depressed patients and 20 comparison subjects to examine possible determinants of lymphocyte proliferation in depression. RESULTS: Depressed patients with lower proliferative responses than their matched comparison subjects had lower depression subscale, anergia subscale, and total scores on the Brief Psychiatric Rating Scale than did patients with higher proliferative responses than their matched comparison subjects. This finding was unexpected and unexplained. Depressed patients with lower proliferative responses than their matched comparison subjects also had fewer obsessions and compulsions and less psychomotor agitation according to the Schedule for Affective Disorders and Schizophrenia interview than did patients with higher proliferative responses than their matched comparison subjects. Stepwise discriminant analysis and cluster analysis contributed little further understanding of the determinants of in vitro lymphocyte proliferation of cells from depressed patients. CONCLUSIONS: Longitudinal studies using multiple serial determinations of mitogen-induced lymphocyte proliferation are the minimal design needed to make this assay useful in further evaluating any immune system changes in depression.

Association of beta-endorphin with specific clinical symptoms of depression.

OBJECTIVE: Abnormalities in plasma concentrations of beta-endorphin-like immunoreactivity (beta-endorphin) have been reported in depressed patients. This study was done to test the hypothesis that specific clinical characteristics of depression are associated with plasma beta-endorphin concentration. METHOD: Plasma beta-endorphin was evaluated in 20 depressed patients diagnosed according to DSM-III-R and in 23 age- and sex-matched comparison subjects, and each was evaluated with the structured Schedule for Affective Disorders and Schizophrenia (SADS). Twelve SADS items involving dysphoric mood and related symptoms were chosen for analysis. RESULTS: Within the group of all 43 subjects and within the depressed group, beta-endorphin level correlated significantly with psychic anxiety and with phobia. In the depressed group only, beta-endorphin also correlated significantly with obsessions/compulsions. Concentration of beta-endorphin was not significantly correlated with score on the Hamilton Rating Scale for Depression or Beck Depression Inventory or with scores on other SADS symptom items, including somatic anxiety, insomnia, subjective anger, overt anger, agitation, psychomotor retardation, panic attacks, appetite loss, or total weight loss. In the group of 23 comparison subjects, beta-endorphin did not correlate with Beck or Hamilton depression score or with any of the SADS clinical variables. CONCLUSIONS: High levels of plasma beta-endorphin may be associated with more severe anxiety, phobia, and obsessions/compulsions in depressed patients.

Blunted growth hormone response to peripheral infusion of human growth hormone-releasing factor in patients with panic disorder.

Patients with panic disorder (N = 11) and age- and sex-matched normal control subjects (N = 11) were challenged with human growth hormone-releasing factor (GH-RF) (1 microgram/kg i.v.) or placebo in random order. The control subjects had significantly increased plasma growth hormone (GH) levels after GH-RF infusion whereas panic disorder patients did not. At 15 and 30 minutes after GH-RF infusion, GH concentrations were significantly higher in the control subjects than in the patients. These findings with GH-RF extend findings from earlier reports that patients with panic disorder show blunted GH response to phobic stimulation and clonidine.

Fatigue, sleep disturbance, disability, and indices of progression of HIV infection.

OBJECTIVE: The authors' objective was to test the hypothesis that fatigue affects the activities and employment of subjects with HIV infection and that indices of immunosuppression and inflammation may have statistical utility in predicting fatigue and sleep disturbance. METHOD: The authors prospectively asked 112 homosexual men (62 HIV-seropositive subjects and 50 HIV-seronegative comparison subjects) to complete a questionnaire on fatigue and sleep disturbance. In addition, hematocrit, WBC count, CD4+ cell number, lactate dehydrogenase, albumin, and total globulin were measured. RESULTS: For HIV-seropositive patients fatigue was significantly more of a problem and interfered more with important activities such as employment and driving than with seronegative comparison subjects. The HIV-infected patients were significantly more likely to be unemployed, to feel fatigued through more hours of the day, to sleep more, to nap more, and to have diminished midmorning alertness. The medical variables could be used to statistically predict fatigue, its interference with daily activities, and employment. CONCLUSIONS: Fatigue and sleep disturbances contribute to morbidity and disability in HIV-infected homosexual men, especially those in CDC stage IV (AIDS-related complex or AIDS). Correlation with measures of immunosuppression and inflammation and comparison between fatigued versus nonfatigued groups suggest the possibility of statistical prediction of fatigue by using these measures. Further study is needed to examine the possibility of eventual specific intervention to clinically treat HIV-related fatigue, sleepiness, and sleep disturbance.

The effects of transdermal nicotine therapy for smoking cessation on depressive symptoms in patients with major depression.

This study examines the effects of transdermal nicotine patches for smoking cessation on depressive and withdrawal symptoms among 38 non-medicated subjects with Major Depressive Disorder. The study was conducted over a 29-day period, which included a 7 day baseline phase, a 14 day treatment phase, and an 8 day placebo phase. During the treatment phase subjects received either active nicotine patches (N = 18) or placebo patches (N = 20) that were administered in a randomized, double-blind fashion. The target quit date (TQD) was day 8. Significantly, more subjects in the placebo group than in the nicotine group resumed smoking following the TQD (50% vs. 22%). There was little evidence for effects of active nicotine patches on measures of mood (HRSD, BDI, POMS) or withdrawal symptoms among subjects that remained abstinent throughout the study (N = 24). Those who resumed smoking had more severe withdrawal symptoms than those who remained abstinent. One patient in the placebo group (n = 20) became more depressed after 2 weeks of abstinence. None of the patients in the nicotine group (n = 18) became more depressed.

Ipsapirone, a 5-HT1A agonist, suppresses REM sleep equally in unmedicated depressed patients and normal controls.

To determine whether ipsapirone, a 5-HT1A agonist, differentially suppresses REM sleep in depressed patients compared with normal controls, we administered placebo, ipsapirone 10 mg, or ipsapirone 20 mg in a double-blind, random order before bedtime in 18 unmedicated patients with depression and 16 age-matched, gender-matched normal controls. Compared to placebo, ipsapirone affected REM sleep measures equally in depressed patients and controls as follows: (1) increased REM latency; (2) reduced total REM percent, REM time, and REM density; and (3) delayed the onset of REM sleep. In addition, ipsapirone had similar effects in patients and controls in other sleep measures: (1) reduced total sleep time; (2) delayed sleep onset time; and (3) increased sleep latency, stage 1%, stage 2%, the amount of stage 3 & 4 sleep in the first non-REM period, and wake time after sleep onset. The study does not support the hypothesis that downregulated 5-HT1A receptors mediate the pathophysiology or sleep disturbances of depression, although further studies are needed as these patients did not differ from controls in baseline sleep measures.

Relationship of mood disturbance to cigarette smoking status among 252 patients with a current mood disorder.

BACKGROUND: The relationship between cigarette smoking and mood has received increasing attention. This retrospective study evaluated the relationship between mood disturbance and cigarette smoking status among patients with a current mood disorder. The association between level of nicotine dependence and severity of mood disturbance was also evaluated among current smokers. METHOD: Retrospective data for 252 patients (63.5% male, 85.0% white) admitted for treatment of a mood disorder at the San Diego Veteran Affairs Mental Health Clinical Research Center between November 1988 and June 1997 were studied. All current cigarette smokers at admission (N = 126) were matched with nonsmokers (N = 126) on the primary DSM-IV Axis I mood disorder diagnosis, admission status (inpatient or outpatient), gender, age (+/- 5 years), and ethnicity. The Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory, and the Profile of Mood States (POMS) were administered to patients on admission. Conditional logistic regression analysis for matched sets with a backward elimination was used to identify factors independently predictive of current smoking status. RESULTS: A greater number of cups of coffee consumed per day (p = .002), a history of alcoholism (p = .004), and higher POMS fatigue subscale scores (p = .007) were predictive of current smoking status. Among current smokers, the HAM-D terminal insomnia item was positively associated with mean number of cigarettes smoked per day (p = .012). CONCLUSION: Cigarette smoking should be addressed in the treatment of patients with a current mood disorder. Smokers experience greater levels of fatigue than nonsmokers. In addition, higher cigarette consumption levels are associated with mild-to-severe symptoms of terminal insomnia.

Gender differences in outpatient research subjects with affective disorders: a comparison of descriptive variables.

BACKGROUND: Gender may play an important role in the etiopathophysiology of psychiatric illness and has become a subject of increasing interest because of its possible effects on biological markers, treatment outcome, and prognosis. Intrigued by this issue and as part of our attempt to further characterize research subjects in San Diego, we evaluated male and female research subjects from our affective disorders clinical research center on a variety of measures. Based on epidemiologic data, we postulated that female and male subjects would be similar to epidemiologic samples and would differ in terms of comorbid diagnoses and that female subjects would be more likely to have had a history of previous treatment. METHOD: The demographic characteristics; coffee, tobacco, and alcohol consumption patterns; symptom patterns; and current and lifetime comorbid DSM-III-R Axis I diagnoses of 124 female and 69 male outpatient research subjects were contrasted. RESULTS: Female research subjects had more comorbid problems with anxiety disorders, were more likely to have been previously treated, and were more likely to have a family history of psychiatric illness. CONCLUSION: Male and female research subjects were remarkably similar with respect to most characteristics assessed but, as postulated, differed in terms of their comorbid diagnoses and prior treatment history.