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Electrocortical and behavioral arousal are separate phenomena subserved by different neural substrata operating in parallel. A comprehensive theory of 'activation' must take into account the relationships between the electrical and behavioral activating systems. In pathological or experimentally induced states paradoxes, resolvable by a theory positing functional interaction between these systems, arise. EEG arousal is directly mediated, in both the waking and sleeping state, by cholinergic mechanisms. Antidepressant withdrawal precipitates cholinergic overdrive; this would account for the apparent disturbances of REM sleep occurring when antidepressants are stopped. Generally, cholinergic overdrive would produce behavioral inhibition but in particular instances it triggers marked psychomotor arousal by mobilizing a 'limbic activating system'. The existence of a monoaminergic 'limbic activating system', system 'A', with the properties attributed to it in this paper, is supported by both clinical and laboratory observations. System 'A' theory provides a parsimonious means of adequately explaining many phenomena. This theory also has in its favor explanatory power and scope. The Cholinergic-Monoaminergic Interaction Theory of antidepressant withdrawal induced activation and of rapidly-cycling manic-depressive illness maintains that system 'A' and a cholinergic inhibitory system interact dynamically, and that excessive monoaminergic function can precipitate excessive cholinergic function and a dearth of monoaminergic function (due to autoregulation) and hence depression. Likewise, excessive cholinergic function is posited to activate monoaminergic systems and hence to secondarily cause behavioral activation. Rapidly-cycling manic-depressive patients, according to the model, develop alternating cholinergic and monoaminergic overdrive states because the homeostatic mechanisms which should serve to maintain, within normal limits, the composite of cholinergic inhibitory and monoaminergic activating influences are defective. Consequently, rather than reaching a reasonable balance compatible with adaptive function there is oscillation between extremes. Each oscillatory movement is actually a move towards the 'golden mean' and is induced by deviation from this ideal but the defective homeostatic mechanisms promote ' perpetual ' overshooting. Lithium and ECT may be useful in the treatment of rapidly-cycling patients as both treatments may down-regulate muscarinic receptors, and otherwise modify cholinergic and monoaminergic systems in ways promoting homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)

The authors describe three patients who developed withdrawal symptoms after discontinuation of antidepressants. Their symptoms were successfully treated with atropine. Central cholinergic overdrive is implicated in the genesis of the symptoms.

A 27-year-old neuroleptic-stabilised schizophrenic patient presented with a three-day history of psychomotor retardation, disturbed sleep, and social and emotional withdrawal following reduction of his anticholinergic dosage; his symptoms had intensified after an increase in neuroleptic dosage, based on a diagnosis of psychotic decompensation. Recognition of a cholinergic syndrome and institution of appropriate anticholinergic treatment resulted in rapid improvement. The clinical distinction between a cholinergic overdrive state and schizophrenic exacerbation, while sometimes difficult, can be critical in selecting appropriate management.

The degree of hypothalamic-pituitary-adrenal (HPA) axis dysregulation in depressed patients with schizoaffective disorder was compared to that seen in patients with major depressive disorder with and without delusional features. The frequency of nonsuppression to dexamethasone was similar for all three diagnostic groups. Maximum postdexamethasone plasma cortisol was greater for delusional depressives, but did not differ between patients with major depressive and schizoaffective disorders. Modest correlations were found between postdexamethasone plasma cortisol levels, severity of illness, age, and recent weight loss, for patients with both major depressive disorder and delusional depression. For schizoaffective patients, associations between postdexamethasone plasma cortisol levels and various measures of severity of illness, but not age and recent weight loss, were found. Although HPA axis dysregulation occurs more frequently in all three of the studied diagnostic groups than in normal individuals, factors contributing to this dysregulation may be qualitatively different for schizoaffective patients.

This article is intended to elucidate some of the neuropathogenetic mechanisms possibly operative in obsessive-compulsive disorder (OCD). Relevant literature is reviewed, with attention to psychologic, and pathologic considerations. Anatomy, neurochemistry, and known functional associations with neuropathological and behavioral abnormalities of implicated brain regions are discussed. The authors propose that dysfunction of neuronal circuits interconnecting the orbitofrontal cortex, basal ganglia/limbic striatum, and thalamus serves a critical role in the pathogenesis of OCD and that obsessive-compulsive symptoms occur when an aberrant positive feedback loop develops in the reciprocally excitatory frontothalamic neuronal interchange, which is inadequately integrated or inhibited by the ventromedial (limbic) portions of the striatum; the ventromedial striatum may serve to modulate activity in the frontothalamic circuit through a negative feedback loop.

Panic and depressive symptoms occur simulataneously in many depressed patients. To study the frequency of this association and to determine whether patients with simultaneous panic and major depression differed from those with only major depressive disorder (MDD) in clinical features and in sleep electroencephalographic (EEG) variables, we evaluated a total sample of 336 patients with MDD. Fifty-eight (17%) had both panic and MDD; 50 had complete data and were matched for age and severity of illness with other patients having only MDD. Patients with simultaneous panic and depression had significantly higher ratings for psychic and somatic anxiety, and rapid eye movement (REM) latencies approximating normal values. Patients with only MDD ( without panic disorder) rated significantly higher in guilt feelings and had shorter REM latencies. Our results suggest that the simultaneous occurence of panic and depression is relatively frequent, is accompanied by differences in sleep EEG variables, and may have implications for treatment.

To evaluate the question of whether "mixed" bipolar disorder is a distinct entity, we compared selected cerebrospinal fluid (CSF) biochemical para- meters from patients with bipolar disorder, mixed, to those with mania and major depression. Fourteen patients in each category (DSM-111) were studied with regard to CSF HVA, SHIAA, sodium, potassium, calcium, and magnesium levels under carefully controlled conditions. CSF HVA, SHIAA, and sodium were found to be significantly higher in manics than in major depressives. Discriminant analysis of the biochemical variables of the mixed affective group identified two biochemically distinct and clinically different subgroups of seven patients each, one resembling the manic group and the other the major depressive group. These findings suggest that mixed affective states do not exist as a separate entity, but are compsed of two subgroups obtained from the manic and major depressive categories.

Caffeine increases anxiety in people with anxiety disorders. To determine whether caffeine exerts a similar effect in depression, the authors compared retrospective reports of caffeine intake and symptoms produced by caffeine ingestion in patients with panic disorder, patients with major depression, and control subjects. Panic patients consumed less caffeine and reported more symptoms than depressed or control subjects. Although depressed patients did not differ from control subjects in caffeine intake or most symptoms, more depressed patients reported that caffeine induced anxiety. These data support prior reports that panic patients have increased sensitivity to caffeine; some depressed patients may also have increased sensitivity.

Clinicians and researchers lack accuracy in assessing psychomotor functions of patients. Several objective monitoring techniques have recently been proposed with the goal of compiling accurate determinations. These include electromyographic determinations of facial expressions of emotion, measurement of speech phonation and pause times, and use of movement-activated recording monitors to quantify motility. Objective psychomotor assessments may improve classification, longitudinal monitoring, treatment selection, and prediction of outcome for patients with depression and mania.

Several authors have suggested that Dexamethasone Suppression Test (DST) non-suppression is related to circadian alternations of hypothalmic-pituitary-adrenal function. Two clinical manifestations of altered circadian rhythms in depressed patients are early morning awakening and diurnal variation in mood. To observe whether these clinical symptom patterns were associated with an increased frequency of abnormal DSTs, we examined post-DST plasma cortisol concentrations and matched clinical ratings of early morning awakening and diurnal variation in mood in 49 patients with major depressive disorder, endogenous subtype. We found no significant association between these clinical and laboratory variables.

We report the utilization of a very sensitive radioimmunoassay for plasma B-END, which has enabled us to examine the suppressibility of B-END-like material, under dexamethasone challenge, on a population of depressed patients. We have found that B-END-like material in plasma is suppressed by dexamethasone in a psychiatric control population, whereas suppression is less likely in endogenously depressed patients. There also appears to be a dissociation between cortisol and B-END measures (tested at 4:00 PM) in the endogenously depressed group.

A "unique" heroin epidemic was claimed to exist among American soldiers in Vietnam in the early 1970s. To assess this claim, in 1972 we simultaneously evaluated heroin use in two similar military populations in the United States and Vietnam and compared findings with previous Vietnam studies. The total percentage ever reporting use of heroin was comparable in both locations. Recent use, however, was significantly higher in Vietnam. Heroin users, regardless of location, were demographically and psychosocially more similar than different. Any conclusion that the heroin epidemic in Vietnam was grossly "unique" seems unwarranted.

The hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in many patients with major depressive disorder (MDD). To determine whether or not a past history of depressive episodes is associated with this dysregulation, we studied the relationships among number of past depressive episodes, number of previous hospitalizations for depression, and number of years since first depressive episode and biological markers of depression (postdexamethasone plasma cortisol levels and dexamethasone suppressor/nonsuppressor status). No significant relationships were detected.

Clinicians historically have considered psychomotor abnormalities as para mount features for the diagnosis of affective disorders. Nelson and Charney [1] reviewed 95 studies to determine distinctive symptoms of major depressive disorder They found that psychomotor retardation was at or near the top of most lists Overall and associates [2], Kendell [3], and Faykel and colleagues [4,5], each identified motor retardation as the one symptom most useful for both classification and prediction of treatment responses. More than half a century ago, Adolf Meyer [6] stated that psychomotor acceleration is the most striking feature associated with mania, and this observation is still accepted. Both DSM-III [7] and the Research Diagnostic Criteria [8] list psychomotor retardation and agitation among items necessary for the diagnosis of depression and mania.

We compared the efficacy of unilateral nondominant (n = 15) and bilateral (n = 31) electroconvulsive therapy (ECT) in melancholia in 46 consecutive, nonrandomly assigned medication-free patients with endogenous depression. Seizure duration was recorded and, if a seizure lasted25 s, the stimulus was immediately readministered. There were more missed or brief seizures that required restimulation with unilateral ECT than with bilateral ECT. After five treatments, blind assessments on the Hamilton Rating Scale for Depression showed a 57% improvement in the bilateral group as compared with a 19% improvement in the unilateral group. The unilateral group received more total treatments (mean = 9.9) than did the bilateral group (mean = 7.7). At the conclusion of all ECT treatments, 72% of patients receiving bilateral ECT were substantially improved and 14% partially improved, compared with 32% of patients receiving unilateral ECT with substantial improvement and 30% partial improvement. This difference between the two groups, however, had disappeared by the time of discharge. Although unilateral ECT may induce fewer side effects, we find bilateral treatments to be more efficacious, at least on a short-term basis.

Mood states and immunity may be related. To investigate the immune status of patients with primary depressive illness, we compared in-vitro lymphocytic responses to three different mitogens in 26 drug-free depressed patients and 20 normal controls of comparable age and sex. We observed a generalized and marked decrease in the lymphocyte mitogenic activity among the depressive group. This defect in lymphocyte function may be indicative of an impairment in cell-mediated immunity in patients with primary depressive illness.

• Several clinical and physiologic associations between depression and diabetes mellitus have been reported. In this study, a potential neuroendocrine association was studied by measuring hypothalamic-pituitary-adrenocortical (HPA) axis activity in patients with diabetes mellitus. Plasma cortisol levels and response to dexamethasone administration were determined in 54 diabetics. Twenty-three (55%) of forty-two 1-mg dexamethasone suppression tests (DSTs) performed in 34 subjects, with eight repeated tests, and two (10%) of twenty 2-mg DSTs demonstrated a blunting of normal suppression. None of a variety of potential demographic, physiologic, or mood factors predicted nonsuppression. This study replicates prior findings that HPA dysfunction occurs in association with diabetes, and invalidates the use of the 1-mg DST as a diagnostic marker for melancholia in patients with diabetes.

SynopsisThe blood counts of 80 patients with depression were examined (50 unipolar, 30 bipolar). Many had reduced numbers of circulating lymphocytes. This abnormality was more common in the unipolar group (52%) than in the bipolar group (27%). When those patients with an abnormal dexamethasone suppression test response in both groups were compared, the relative and absolute lymphocyte counts were significantly lower in unipolars. Although cortisol hypersecretion may reduce lymphocyte numbers it is not yet clear whether the findings can be satisfactorily explained in this way.

In the late 1960s and early 1970s, a number of investigators began to utilize the dexamethasone suppression test (DST) as a neuroendocrine laboratory aid for identifying patients with endogenous depression (melancholia; vital depression) (Carroll, 1972; Carroll et al., 1976a, 1976b; Stokes, 1972). The rationale for this research strategy was that normal subjects have limbic-hypothalamic-pituitary-adrenal axis (L-H-P-A) suppression for more than 24 h after receiving a small oral dose of dexamethasone (1 or 2 mg). In contrast, approximately 40 to 70% of patients with melancholic pathophysiology have L-H-P-A non-suppression, reflected by plasma cortisol concentrations greater than 5 μg/d1 (using a competitive protein binding assay) or 4 μg/d1 (with most radioimmunoassays). Most early DST studies evaluated the diagnostic efficacy of the test (Carroll et al., 1981). Pilot studies also considered whether the test had value in objectively monitoring treatment progress, providing an early prediction of treatment outcome, selecting specific somatic treatments, indicating prognosis, aiding in diagnostic reclassification, or as a variable in pharmacological experiments (Greden et al., 1980, 1981a; Carroll et al., 1980a, 1980b; Goldberg et al., 1980).

Disinhibition of the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system is characterized by high CSF cortisol concentrations and abnormal dexamethasone suppression test (DST) results. These two variables are strongly correlated. Abnormal DST results are strongly associated with serious suicidal behavior in melancholic patients. Low CSF 5-HIAA concentrations are dissociated from abnormal DST results. Thus the neuroendocrine disturbance and the neurotransmitter disturbance appear to be unrelated biochemical markers in depressed patients. Since there is evidence that both markers may predict suicide behavior, however, further studies of each marker in the same patients should be performed.

Amphetamine sulphate (0.1 mg/kg, i.v.) produced no consistent change in plasma cortisol levels in 21 depressed patients. Seven patients with endogenous depression (melancholia) were matched with seven patients with non-endogenous depression; there was no difference in the cortisol response to amphetamine between these two groups.

Recent work suggests that the simultaneous occurrence of major depressive disorder (MDD) and panic disorder (PD) may be of relevance for clinical findings, therapeutic outcome, and prognosis. It is of interest to know whether or not this relevance extends to biological findings. We addressed this question through comparison of serial Dexamethasone Suppression Test (DST) results in patients who had either MDD alone or simultaneous MDD and PD. We were unable to describe differences between the groups.

In order to discuss in detail the relationship between functional markers and the origins of depression, attention was restricted to a limited number of measures of sleep and neuroendocrine function. As most of these functional markers vary with a circadian rhythm, it is appropriate to begin by considering changes in circadian rhythms in depression.

Many patients with major depressive disorder (MDD) develop state-dependent hypotbalamicpituitary-adrenal (HPA) axis dysregulation (Carroll et al. 1981). A complex interaction of factors contributes to this abnormality. Severity of illness (Kumar et al. 1986; Meador-Woodruff et al. 1987; Miller and Nelson 1987), age (Oxenkrug et al. 1983; Davis et al. 1984; Lewis et al. 1984), and degree of recent weight loss (Keitner et al. 1985; Krishnan et al. 1985b) are seemingly three of the most important determinants. Severity of depression has been shown to correlate moderately with and to contribute significantly to the total variance of postdexamethasone cortisol levels in patients with MDD, at both the pituitary and adrenal levels of the HPA axis. Many reports, however, have found this correlation by studying subjects who were operationally defined as either Dexamethasone Supp~ss~on Test (DST) nonsupp~ssors or suppressors. DST nonsuppressors have high postdexamethasone cortisol levels by definition and

Higher electromyographic (EMG) activity levels of corrugator and zygomatic face muscles have been reported to be pretreatment predictors of better clinical outcome in depressed patients. We tested this possibility in 29 drug-free, rigorously diagnosed subjects by measuring low-level EMG activity of corrugator and zygomatic muscles during resting and three imagery states (happy, typical day, sad). All patients had major depressive disorder, endogenous subtype. Good responders had significantly higher pretreatment EMG zygomatic values and different EMG profiles. Our findings replicate and expand prior reports.

The prevalence of Schneiderian first-rank symptoms (FRS) in 294 consecutive admissions to a research unit was evaluated with reference to their diagnostic distribution (SADS/RDC). Thirty-five of 58 patients with schizophrenia had FRS, as compared to nine of 190 patients with major depressive disorder. All patients with two or more FRS received a diagnosis of schizophrenia. In the absence of organic or toxic etiology, the specificity of FRS for schizophrenia was 95% and their predictive value was 90%. These findings indicate that FRS should be regarded as strongly suggestive of schizophrenia in the absence of an organic syndrome.

• To study whether facial electromyographic (EMG) activity during affective imagery differed between normal subjects and depressive subtypes, we evaluated EMG responses in 29 normal controls, 37 endogenously depressed patients, and 26 nonendogenously depressed patients. Different imagery states produced more distinctive EMG patterns in normal controls than in depressed patients. Patients with endogenous depression had EMG levels that differentiated them from normal subjects and had significantly greater absolute values than the nonendogenous group in corrugator happy and corrugator sad imagery trials. Intensity of sad and happy imagery, age, and severity of depression did not systematically correlate with EMG activity among depressive subtypes.

Endogenous depressives with abnormal dexamethasone suppression tests (DSTs) respond better to somatic antidepressant treatments than those with normal DSTs. Whether the DST also aids in the selection of specific antidepressants has not been determined. A pilot report suggested that patients with abnormal DSTs might be noradrenaline-deficient and respond preferentially to imipramine or desipramine, whereas those with normal DSTs might be serotonin-deficient and respond best to amitriptyline or clomipramine. Attempting to replicate this observation, we studied 26 patients diagnosed with Research Diagnostic Criteria as major depressive disorder, endogenous subtype, and with DSM-III as having melancholia. All were drug-free during baseline evaluation. All had abnormal DST results, with post-dexamethasone plasma cortisol levels exceeding 5 microgram/dl. We treated subjects with either imipramine or amitriptyline and compared clinical response with weekly Hamilton Depression Rating Scales, completed by raters blind to both DST results and the research question. Thereapeutic plasma levels were documented. We found no significant differences in treatment response between the subgroups. Twenty of the 26 subjects did well. The imipramine-treatment group failed to have either earlier response or better final outcome. These data fail to replicate suggestions that DST results assist in the selection of either imipramine or amitriptyline.

The authors assessed by questionnaire the alcohol use of 1,873 U.S. soldiers in the United States and Viet Nam. According to operational definitions based on total ethyl alcohol consumption and several behaviors associated with drinking, 7 percent were classed as alcoholics, 5 percent as borderline alcoholics, and 24 percent as potential alcoholics. Contrary to popular stereotypes, there was a disproportionate number of younger and lower ranking soldiers in these three groups; there was also a positive relationship between drinking and use of illicit drugs across groups. The authors state that future studies of alcohol use should include determinations of total ethyl alcohol intake to permit generalizability of their results. Language: en

The corrugator muscle region of the forehead has special significance in producing facial expressions associated with depression. Darwin observed in 1872 that contractions in the corrugator region produce peculiarly formed wrinkles on the forehead, referred to as "Omega Melancholium." In the present study, results from 61 right-handed, drug-free women with major depressive disorder showed a significant positive correlation between facial corrugator EMG values and psychomotor agitation. Results were not due to differences in severity of depression. These data offer preliminary evidence that agitation is reflected in corrugator muscle activity and may explain the "Omega sign" of melancholia.

The hypothalamic-pituitary-adrenal (HPA) axis has been meticulously investigated in psychiatric illness, particularly in depression (Sachar et al. 1973; Sachar 1975). The Dexamethasone Suppression Test (DST) as a measure of the integrity of inhibitory feedback loops (Carroll et al. 1981; Stokes et al. 1984; Arana et al. 1985) of the HPA axis has received much attention. Though some controversy remains (Arana et al. 1985), there appears to be a general consensus that moderate to severe major depressive disorder (MDD), particularly in older inpatients, will lead to disinhibition of the HPA axis in a significant number of patients. On tbe other hand, the DST in patients with panic attacks (PA)-panic disorder (PD) and agoraphobia-has consistently yielded suppression in a

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.

The borderline personality concept has evolved from a term used to describe a neurotic- psychotic borderland (Knight 1963), or an al- most but-not-quite schizophrenic process (Hock and Polatin 1949), to a more precise and op- erationally defined syndrome (American Psy- chiatric Association, 1980; Gunderson 1982). Affective changes are a major and consistent clinical feature in most descriptions of border- line personality disorders (BPD). Major de- pressive disorder (MDD) or other DSM-III Axis I diagnoses, including panic disorder, may be present in a significant number of BPD patients, perhaps in the majority (Carroll et

Four hundred thirty-eight subjects underwent an overnight dexamethasone suppression test (DST) to standardize the test for the diagnosis of melancholia (endogenous depression). Abnormal plasma cortisol concentrations within 24 hours after dexamethasone administration occurred almost exclusively in melancholic patients. The best plasma cortisol criterion concentration, above which a DST result may be considered abnormal, was 5 microgram/dL. The optimal dose of dexamethasone was 1 rather than 2 mg. Two blood samples obtained at 4 and 11 PM after dexamethasone administration detected 98% of the abnormal test results. This version of the DST identified melancholic patients with a sensitivity of 67% and a specificity of 96%. Baseline nocturnal plasma cortisol concentrations were not useful. Abnormal DST results were found with similar frequency among outpatients and inpatients with melancholia; but they were not related to age, sex, recent use of psychotropic drugs, or severity of depressive symptoms. Extensive evidence validates this practical test for the diagnosis of melancholia.

A population of 747 functioning military personnel was surveyed at an army installation in the United States to determine previous use of illicit drugs and associated attitudes toward treatment. Based on self-reported drug use, seven subgroups with distinct patterns were delineated and statistically compared. Demographic distinctions among these subgroups were frequently pronounced, as were prevailing attitudes toward traditional medical and psychiatric treatment of drug abuse. These distinctions have obvious implications in planning and conducting drug abuse prevention, treatment, and educational programs.

A survey to determine patterns of drug use and attitudes toward treatment was conducted shortly before the establishment of a drug abuse control program in the Army. Eight months after the program was begun, the survey was repeated, using a similar population at the same military installation. Comparison of the surveys revealed no immediate beneficial effects of the program. Reports of previous drug use had increased. The number of those who intended to use nonopiate drugs in the future had increased; willingness to seek treatment remained unchanged and a great deal of skepticism still prevailed.