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Background: Anabolic androgen steroid abuse is associated with multiple psychiatric symptoms and is a significant public health problem. The biological mechanisms underlying behavioral symptom development are poorly understood., Subjects and Methods: We examined levels of monoamine metabolites, neurohormones, and neuropeptides in the cerebrospinal fluid (CSF) of 17 healthy men, at baseline and following 6 days of methyltestosterone (MT) administration (3 days of 40 mg/d, then 3 days of 240 mg/d). Subjects received MT or placebo in a fixed sequence, with neither subjects nor raters aware of the order. Potential relationships were examined between CSF measures, CSF MT levels, and behavioral changes measured on a visual analog scale., Results: Following MT administration, levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly lower (mean +/- SD, 103.8 +/- 47 vs 122.0 +/- 50.7 pmol/mL; P<.01), and 5-hydroxyindoleacetic acid (5-HIAA) levels were significantly higher (mean +/- SD, 104.7 +/- 31.3 vs 86.9 +/- 23.6 pmol/mL; P<.01). No significant MT-related changes were observed in CSF levels of corticotropin, norepinephrine, cortisol, arginine vasopressin, prolactin, corticotropin-releasing hormone, beta-endorphin, and somatotropin release-inhibiting factor. Changes in CSF 5-HIAA significantly correlated with increases in "activation" symptoms (energy, sexual arousal, and diminished sleep) (r = 0.55; P =.02). No significant correlation was observed between changes in CSF and plasma MT, CSF MHPG, and behavioral symptoms., Conclusions: Short-term anabolic androgenic steroid use affects brain neurochemistry, increasing CSF 5-HIAA and decreasing MHPG. Changes in 5-HIAA levels caused by anabolic androgenic steroids are related to the behavioral changes we observed. In this small sample, we did not observe a significant relationship between behavioral measures and either dose of MT or CSF and plasma levels of MT.

Background: Multiple lines of evidence suggest that brain serotonergic systems may be disturbed in seasonal affective disorder (SAD). Previously, we found that the serotonergic agent meta-chlorophenylpiperazine (m-CPP) produced increases in activation and euphoria in depressed patients with SAD, but not in patients with SAD following light treatment or in the summer, nor in healthy control subjects in any condition. In the present study, we attempted to replicate and extend this finding using better methods., Methods: Seventeen outpatients with SAD and 15 control subjects underwent successive 3-week periods of bright light treatment and light avoidance in a randomized order. During the third week of each condition, on 2 different occasions, subjects were admitted to the hospital for a night of sleep (core temperatures were recorded), followed by infusions of m-CPP (0.08 mg/kg) or placebo the next morning. Dependent measures included the 24-item National Institute of Mental Health Self-Rating Scale, plasma corticotropin, cortisol, prolactin, growth hormone, and norepinephrine concentrations, and core temperatures., Results: Meta-chlorophenylpiperazine produced (1) significant increases in "activation-euphoria" ratings only in depressed patients with SAD in the untreated condition and (2) blunted corticotropin and norepinephrine responses in patients with SAD compared with controls across both light treatment conditions. In both groups, light treatment was associated with significant reductions in nocturnal core temperatures, which were correlated with similarly significant reductions in mean diurnal growth hormone concentrations. In patients with SAD, (1) the reductions in nocturnal core temperatures also were correlated with the reductions in baseline depression ratings and (2) the reductions in mean growth hormone concentrations were significantly smaller compared with controls., Conclusions: The abnormal m-CPP-induced activation-euphoria responses represent a replicated state marker of winter depression in patients with SAD. The blunted m-CPP-induced responsiveness of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system may represent traitlike abnormalities. The improvements in mood following light treatment in patients with SAD seem to be associated with the lowering of nocturnal core temperatures. The findings, although not easily explained based on a uniform abnormality of serotonin receptors, are nonetheless compatible with the notion that selected regions of the central nervous system are deficient in serotonin transmission during winter depression.

Background: We examined the effect of high-dose selegiline in 16 treatment-resistant older depressive patients. We hypothesized that selegiline, at a dosage of 60 mg/d, would be at least partially effective but that the higher doses would not maintain the monoamine oxidase B selectivity observed with the lower doses of selegiline., Methods: Sixteen treatment-resistant subjects (mean [+/- SD] age, 65.6 +/- 9.3 years) entered a double-blind, randomized, crossover study of placebo vs 3 weeks of selegiline at a dosage of 60 mg/d. Objective measures of mood and behavior were obtained in all subjects, and 10 of the subjects underwent repeated lumbar punctures for analysis of monoamine metabolites in the cerebrospinal fluid., Results: Objective measures of mood and behavior revealed significant improvement in the Hamilton Depression Rating Scale score (37.4% decrease), the Global Depression score (22.7% decrease), and the Brief Psychiatric Rating Scale score (19.3% decrease); subjective behavioral measures, however, did not show significant improvement during the 3-week medication trial. Cerebrospinal fluid values revealed a statistically significant drop in 3-methoxy-4-hydroxyphenylglycol (51%) and 5-hydroxyindoleacetic acid (17%) levels, and there was a significant lowering of systolic blood pressure on standing (15%), but these changes were not accompanied by clinical side effects., Conclusions: Our results suggest that high-dose selegiline can be an effective antidepressant in treatment-resistant older depressive patients. While the selegiline dose required has nonselective monoamine oxidase effects and thus would not be free of possible tyramine interactions, other advantages suggest that further investigations with selegiline are warranted in this population.

Objective: To explore serotonin function in patients with schizophrenia during typical and atypical neuroleptic treatment. We hypothesized that clinically relevant doses of the atypical neuroleptic clozapine would attenuate responses to the serotonin agonist m-chlorophenylpiperazine (m-CPP)., Design and Interventions: m-CPP or placebo was administered intravenously over 90 seconds to patients who had been receiving no medications for at least 3 weeks. m-CPP was also administered during treatment with the typical neuroleptic fluphenazine and the atypical neuroleptic clozapine., Patients: Fifteen inpatients (two women and 13 men) who met DSM-III-R criteria for chronic schizophrenia (n = 13) or schizoaffective disorder (n = 2) participated in the study. Mean age (+/- SD) was 33.8 +/- 8.0 years., Main Outcome Measures: Measures of m-CPP effects included plasma cortisol and prolactin, body temperature, and the Brief Psychiatric Rating Scale (BPRS). The final BPRS total score at approximately 12 weeks of treatment was used to assess response to clozapine., Results: m-CPP infusion significantly increased plasma cortisol and prolactin levels in drug-free patients. There was a range of behavioral responses while drug-free, but no statistically significant effects on BPRS total or BPRS factor scores. Clozapine treatment significantly blocked neuroendocrine responses to m-CPP, whereas fluphenazine had no effect. Clozapine also appeared to attenuate behavioral responses., Conclusions: These results demonstrate that clozapine treatment has potent serotonin antagonist effects in patients with schizophrenia. This may be related to clozapine's therapeutic effects since patients with greater cortisol response to m-CPP while drug-free had a better subsequent response to clozapine.

Preclinical and clinical evidence supports a theory of serotonin (5-hydroxytryptamine [5-HT]) dysregulation in bulimia. We therefore studied the prolactin (PRL) and cortisol responses following challenges with the postsynaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), 0.5 mg/kg orally, the 5-HT precursor L-tryptophan, 100 mg/kg intravenously, and placebo in a group of 28 normal weight bulimic patients and 16 healthy controls. Patients with bulimia, regardless of the presence of major depression, had significantly blunted PRL responses following m-CPP administration compared with those in controls. In contrast, only bulimic patients with concurrent major depression had significantly blunted PRL responses following L-tryptophan administration compared with those in nondepressed bulimic patients and controls. Cortisol responses following m-CPP were not significantly different for bulimic patients vs controls, although there was a trend toward blunted cortisol responses following L-tryptophan administration in the depressed bulimic patients. These differences in neuroendocrine responses were not related to differences in age, percent of average body weight, medications, time of day, peak plasma drug levels, or baseline estradiol levels. Seasonal variations in PRL responses to both agents were identified, although covariation for season did not alter the group differences. The PRL responses following m-CPP administration were inversely correlated to baseline cortisol levels in the bulimic patients, but not in the controls, suggesting a dampening effect by hypothalamic-pituitary-adrenal axis dysfunction on postsynaptic 5-HT receptor sensitivity. The reasons for the differing hormonal responses to these two serotonergic agents may relate to differential involvement of presynaptic and postsynaptic mechanisms, 5-HT receptor subtypes, and anatomical loci of action. The blunted PRL responses to m-CPP administration suggest that postsynaptic 5-HT receptor sensitivity is altered in bulimia nervosa, and that similar alterations in 5-HT receptors at or above the level of the hypothalamus may contribute to binge eating and other behavioral symptoms.

In light of prior data that the central administration of vasopressin in animals is associated with abnormal persistence of behaviors acquired under aversive conditioning, we studied the secretion of arginine vasopressin into the cerebrospinal fluid and plasma in patients with obsessive-compulsive disorder and controls. Patients with obsessive-compulsive disorder had significantly elevated basal levels of arginine vasopressin in the cerebrospinal fluid and significantly increased secretion of arginine vasopressin into the plasma in response to hypertonic saline administration. Moreover, seven of 12 patients with obsessive-compulsive disorder showed a loss of the normal linear relationship between plasma arginine vasopressin level and osmolality. In addition, cerebrospinal fluid corticotropin releasing hormone, which has synergistic effects with arginine vasopressin centrally and at the pituitary gland, was also significantly elevated in patients with obsessive-compulsive disorder compared with controls.

Treatment with fluoxetine hydrochloride was compared with treatment with clomipramine hydrochloride in two groups of patients with obsessive-compulsive disorder using two different experimental designs. In the first group of 11 patients with obsessive-compulsive disorder studied using a randomized, double-blind, crossover design, treatment with fluoxetine for 10 weeks was found to produce therapeutic effects similar to treatment with clomipramine for 10 weeks. There were significantly fewer total side effects reported during fluoxetine than clomipramine treatment. Drug tapering and placebo substitution in the 4-week crossover interval phase led to substantial relapses in obsessive-compulsive disorder symptoms and depression. Furthermore, responses to the second drug took as long to occur as responses to the first drug, although both drugs are thought to act by a common mechanism, serotonin uptake inhibition. A second group of 21 patients with obsessive-compulsive disorder that had been previously stabilized on clomipramine treatment with at least partial benefit were crossed over to fluoxetine treatment in a double-blind fashion. After 10 weeks of fluoxetine administration, most patients manifested behavioral rating scores of obsessive-compulsive disorder and depressive symptoms that were comparable with precrossover ratings completed during clomipramine treatment. A significant exacerbation in obsessive-compulsive disorder and depression ratings as well as a similar lag in therapeutic efficacy were also noted in this second cohort of patients with obsessive-compulsive disorder. Platelet 5-HT concentrations were reduced 95% during both clomipramine and fluoxetine treatment periods. These results suggest that fluoxetine may represent a viable alternative to clomipramine in the treatment of obsessive-compulsive disorder, although further studies with larger sample sizes are needed.

In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessive-compulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.

College students in two separate studies had platelet monoamine oxidase (MAO) activity determinations and average evoked potential (AEP) measurements taken. On the basis of Minnesota Muliphasic Personality Inventory (MMPI) or Research Diagnostic Criteria (RDC) evaluations, psychopathology, particularly affective disorder, was found to be more prevalent among both persons with the combination of low MAO activity and AEP augmenting and those with high MAO activity and AEP reducing. The same pattern is apparent whether students were selected for extremely high or low MAO activity (study 1) or for elevated or normal MMPI scores (study 2). Some psychiatric patient groups also show this pattern. An interactive model of sensation-seeking and sensory inhibition is presented.

During depressive episodes, patients show both qualitative and quantitative changes in how information is processed. Depressed patients appear to use weak or incomplete encoding strategies to organize and transform events to be remembered. This makes these events less memorable. If the depressed patient is provided organization and structure, then learning-memory deficits are not apparent. Disruptions in arousal-activation in depression can account for these cognitive impairments.

The occurrence of behavioral disturbances during four-week treatment of depressed patients with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine sulfate (N = 14), the selective MAO-type A inhibitor, clorgyline (N = 12), and the partially selective MAO-type B inhibitor, pargyline hydrochloride (N = 13), was studied. Behavioral disturbances were encountered during treatment with each of the MAO-inhibiting drugs, with an overall incidence of 15% (six of 39 patients). All but one episode met criteria for mania or hypomania. Patients with bipolar illness experienced significantly greater incidences of behavioral disturbances in comparison with patients with unipolar illness (35.3% v 4.5%, respectively). The earliest latency to onset of a behavioral disturbances was 18 days, whereas the mean latencies were 22 to 26 days. Episodes of hypomania were observed after discontinuation of drug treatment in individual patients with unipolar and bipolar illness. Repeated MAO-inhibitor treatment, as part of a crossover study of clorgyline and pargyline, produced an increased severity of behavioral disturbances and a significantly shortened latency to onset.

We compared the cognitive and behavioral responses to three intravenous doses of scopolamine (0.1, 0.25, and 0.5 mg) and placebo of ten patients with dementia of the Alzheimer type (DAT) and ten age- and sex-matched elderly control subjects. The patients with DAT showed significant behavioral and cognitive but not physiologic changes at a lower scopolamine dose (0.25 mg) than did the normal elderly controls. Cognitive tests of new learning and semantic knowledge revealed significant impairments at the 0.25-mg scopolamine dose in the patients with DAT, while the responses of the control population were essentially unchanged. Behaviorally, mild euphoria, motor incoordination, and hostility occurred in the patients with DAT but not the controls at the 0.25-mg dose. These differences were unrelated to peripheral physiologic changes produced by the different scopolamine doses. These results indicate that central nervous system functions such as cognition and certain elements of behavior are more sensitive to temporary cholinergic blockade in patients with DAT than in normal age-matched controls. We review implications concerning the status of central cholinergic function in patients with DAT in light of neuropathologically demonstrated cholinergic system lesions in DAT.

Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.

Four hundred college men were screened on a measure of vigilance, the Continuous Performance Test (CPT). The individuals with good and poor attention (the upper and lower 5% of the CPT score distribution) were compared on multiple measures of psychiatric disturbance, cognition, and psycho-physiologic function. The attention dysfunction group (lower 5%) had a higher incidence of symptoms of hyperactivity both in childhood and as adults, but had no higher incidence of other psychopathology as assessed with either the Research Diagnostic Criteria or the Minnesota Multiphasic Personality Inventory. Cognitive differences between the lower and upper CPT groups, including differences on Wechsler Adult Intelligence Scale subtests, the Stroop test, reaction time, and evoked potentials, substantiated an attention dysfunction syndrome. Thus, attentional dysfunction in young adults seems more closely linked to hyperactivity than to current psychopathology.

To evaluate further the basis for the reduced activity of platelet monoamine oxidase (MAO) found in chronic schizophrenic patients, a number of characteristics of the enzyme were compared between patients and controls. Equivalent and statistically significant reductions in activity of the enzyme were found in the patients when tyramine and benzylamine were used as the substrates in comparison to previously reported reductions with tryptamine as the substrate. Michaelis constants for platelet MAO from chronic schizophrenic patients with reduced enzyme activity were not different from controls. Dialysis of the enzyme from patients and controls yielded no changes in activity. Studies of other platelet enzymes, including succinate dehydrogenase, cytochrome C reductase, and lactate dehydrogenase in patients, normal controls, and a subgroup of normal controls with reduced MAO activity, showed no parallel reductions in activity in patients or controls with low MAO activity. These findings suggest that the reduced MAO activity found in chronic schizophrenic patients is apparently not accounted for by nonspecific changes in platelets or platelet mitochondria.

IgG reactive with somatostatin 1-14 was identified in human plasma by enzyme linked immunosorbent assay. From a sample of 25 subjects, six (60%) of ten individuals with major depressive disorder demonstrated antibody reactive with somatostatin 1-14, in contrast to one (7%) of 15 controls. Overall, antisomatostatin reactivity was significantly higher in patients with major depressive disorder (0.233 +/- 0.177) than in the normal volunteers (0.084 +/- 0.039; t = 3.18, P less than .01). Antisomatostatin IgG was isolated by affinity chromatography. The recognition site for somatostatin was retained by F(ab)'2 fragments. Although there has been little previous exploration of the existence of antibodies to endogenous neuropeptides, such antibodies could prove of relevance to neuropsychiatric and other human disorders.

Plasma cortisol responses to the intravenous administration of clonidine hydrochloride and placebo were evaluated in depressed patients and controls. Depressed patients had higher mean baseline cortisol levels than controls. Cortisol levels decreased during the morning study period following both placebo and 2 micrograms/kg of clonidine hydrochloride in the depressed patients, but the cortisol decrease was sixfold greater on the day of clonidine administration; these placebo-clonidine differences were statistically significant, whether calculated on an absolute decrement basis or as a percent change. In contrast, controls responded to clonidine with only a 1.5-fold greater cortisol reduction than that found after placebo, a nonsignificant difference from the day of placebo administration. Reductions in the concentration of plasma 3-methoxy-4-hydroxyphenylglycol following clonidine administration were significantly negatively correlated with baseline plasma cortisol levels, raising the possibility that abnormalities in the responsiveness of the alpha 2-noradrenergic system may be associated with the hypothalamo-pituitary-adrenal (HPA) axis dysfunction found in depressed patients.

There have been conflicting reports on the effects of naloxone hydrochloride in patients with dementia of the Alzheimer type (DAT). In addition, none of the naloxone studies in DAT used doses of 2.0 mg/kg or more, the amount necessary to produce reliable cognitive and behavioral changes in young normal subjects. In a randomized, double-blind, placebo-controlled study, 12 patients with DAT were administered naloxone hydrochloride in doses of 5 micrograms/kg, 0.1 mg/kg, and 2.0 mg/kg, with detailed evaluation of its behavioral and cognitive effects using measures selected for their potential relevance to DAT and the known effects of blockade of endogenous opiate systems. None of the measures of motor performance, attention, memory, learning, or recognition showed improvement with naloxone. Increased inappropriate verbal productions were noted after 0.1 mg/kg of naloxone hydrochloride. Patients became irritably activated after this dose, which may account for the altered verbal behavior in this study and also for some of the changes suggesting cognitive improvement in prior studies. Differences in the sensitivity and dose dependency of the behavioral effects in patients with DAT compared with prior studies in young normal subjects merit further investigation.

Hypotheses of involvement of the endogenous opioid system (EOS) in the regulation of human behavior suggest that functional blockade of the EOS should have behavioral consequences. Clinical administration of the opiate receptor antagonist naloxone hydrochloride, however, has had little or inconsistent behavioral effects in normals. This may be attributable to the use of doses insufficient to yield a complete EOS blockade. To assess this explanation, normals were administered increasing doses of naloxone hydrochloride (0.3 to 4 mg/kg) in a single-blind design. Significant dose-dependent behavioral, hormonal, and physiological effects were found. With increasing doses of naloxone, volunteers demonstrated increasingly dysphoric affects, a deterioration of performance on memory testing, increasing systolic BP and respiratory rate, and increasing plasma cortisol and growth hormone levels. These results are consistent with the expected effects of increasing EOS blockade, and thus suggest that lower doses of naloxone used in previous clinical studies may not have been sufficient to produce a complete EOS blockade. Specifically, they suggest involvement of the EOS in the tonic regulation of normal human mood, memory, BP, respirations, and plasma growth hormone and cortisol levels.

The serotonin agonist m-chlorophenylpiperazine (mCPP) was administered intravenously to 12 patients with Alzheimer's disease and ten age-matched controls. It produced distinct behavioral effects in both treatment groups; however, significantly greater responsivity to mCPP was found in patients with Alzheimer's disease than in controls in measures of psychomotor activation, restlessness, and perceptual abnormalities. Significant and similar increases in plasma prolactin and cortisol levels were found in both patients with Alzheimer's disease and controls following the administration of mCPP vs placebo. Furthermore, blood pressure and pulse changes following mCPP were not significantly different between the groups. Elderly controls, however, did show a significantly greater temperature response following mCPP than did patients with Alzheimer's disease. The overall cognitive effects of mCPP were minimal; however, mCPP produced significantly greater worsening in recent memory and knowledge memory in patients with Alzheimer's disease than in controls. These findings could not be explained by pharmacokinetic differences across populations, because plasma concentrations of mCPP were similar in patients with Alzheimer's disease and controls. The increased behavioral responsivity but unchanged neuroendocrine or other physiologic responsivity to mCPP may be related to damaged brain serotonin neurons or other neuronal systems that interact with serotonin neurons that have been found in postmortem and biopsy studies of patients with Alzheimer's disease.

Fourteen patients with obsessive-compulsive disorder (OCD) were studied with all-night sleep EEG recordings. Nine of these patients reported abnormal sleep patterns before the polygraphic study. Analysis of the sleep records disclosed significantly decreased total sleep time with more awakenings, less stage 4 sleep, decreased rapid-eye-movement (REM) efficiency, and shortened REM latency compared with those of a group of age- and sex-matched normal subjects. These abnormalities generally resembled those of an age-matched group of depressed patients, although significant differences remained. These findings suggest that such sleep abnormalities as shortened REM latency may not be entirely specific for primary affective illness. They also point to a possible biological link between OCD and affective illness.

Twenty boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind, random-order, crossover design. Half the boys also met criteria for conduct disorder. Dextroamphetamine produced immediate and marked improvement in disruptive, overactive behaviors. Fenfluramine had no effect on any behavioral measure at either the low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine levels. It reduced urinary epinephrine levels as well, an effect opposite to that of dextroamphetamine. These findings suggest that different mechanisms of action are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin levels. Despite the structural similarity of the two drugs, some common overall effects on catecholamine metabolism, and similar effects on weight, fenfluramine had none of the motor activity or therapeutic effects of dextroamphetamine.

Smooth pursuit eye tracking impairment has been observed in the major psychoses, particularly schizophrenia. To understand better the relationship of smooth pursuit disruption to personality dispositions linked to psychiatric syndromes and to two other "marker variables" associated with psychosis (low platelet monoamine oxidase [MAO] activity and poor performance on the continuous performance task [CPT]), we studied the psychologic, biochemical, and psychophysiologic correlates of impaired smooth pursuit tracking in two nonpsychiatric patient populations. One sample consisted of 67 volunteers screened for extreme values in a distribution of platelet MAO activities, and the second included 29 volunteers screened for extreme scores on the CPT. An aggregate of about 5% of both samples showed clearly dysfunctional smooth pursuit. Eye tracking dysfunction did not seem to be related to either MAO or CPT performance in either study. Both studies were consistent in showing that subjects with impaired smooth pursuit eye tracking had a psychologic profile characterized particularly by social introversion.

Twelve patients with dementia of the Alzheimer type received two-hour infusions of placebo and the muscarinic cholinergic agonist arecoline hydrobromide at rates of 1, 2, and 4 mg/h in a double-blind, randomized fashion. These infusions resulted in dose-dependent physiologic and neuroendocrine effects consistent with central cholinergic stimulation. Infusions were generally well tolerated. No statistically significant improvement in performance on most cognitive tasks assessing knowledge memory and episodic learning and memory was observed at any dose, although marginal improvement in picture recognition ability and in ratings of word-finding were observed at the lower doses. Psychomotor activation and slightly improved affect were reliably observed at the lower doses, whereas increasing psychomotor retardation was observed at the highest dose. The data support a role for central cholinergic modulation of some aspects of cognition, behavior, and affect in this population. The apparent greater behavioral sensitivity of patients with Alzheimer's disease in comparison with subject populations previously studied, as well as the altered dose responsiveness, merit further study in relationship to normal aging.

Five women with primary, major, bipolar affective disorder, characterized by rapid mood cycles and nonresponsiveness to conventional drug treatments, including lithium carbonate, were given low doses (2.5 to 10.0 mg/24 hr) of clorgyline, a selective inhibitor of monoamine oxidase type A. In four patients, clorgyline, along or in combination with lithium carbonate, prolonged the duration and lessened the severity of mood cycles. One patient experienced prolonged mania while receiving clorgyline therapy. Clorgyline-induced remissions have lasted from three to more than 12 months.

The Rorschach was administered to 16 bipolar and 13 unipolar patients hospitalized during a depressive episode. Two contrasting styles of Rorschach responding differentiated the two patient groups. The bipolar style of response is characterized by selective attention to the more objective aspects of the inkblots, while the unipolar style of response is characterized by a more subjective approach. Primary response to color was found only in the protocols of bipolar patients. The styles of response were discussed in relation to other studies showing similar results based on self-assessment and clinical tests. It was suggested that perceptual-cognitive structuring of the external environment may be related to, or predispose, mood levels.

In an intensive multidrug, multidose study, nine elderly depressed patients were administered 0.1, 0.25, and 0.5 mg of scopolamine hydrobromide, 1 mg of oral lorazepam, and placebo in a double-blind investigation aimed at assessing the status of the central cholinergic nervous system in geriatric depression. Significant cognitive and behavioral effects of scopolamine were observed only at the high dose (0.5 mg), while lower doses and lorazepam showed no significant differences from placebo. Cognitive deficits caused by scopolamine were in the areas of new learning, access to semantic memory, vigilance, and continuous performance. Behavioral effects consisted of activation, restlessness, and anxiety, but there was no significant effect on depressed mood. These results suggest that elderly depressed patients with mild to moderate cognitive impairment seem to be more similar to previously studied elderly controls rather than to patients with Alzheimer's disease in their reaction to short-term cholinergic blockade, and suggest that the cognitive and mood changes often seen in geriatric depression may involve factors other than disturbed muscarinic cholinergic mechanisms.

The sympathetic nervous system was evaluated in 11 primary autistic patients and their families. The plasma levels of norepinephrine (NE), the neurotransmitter of the sympathetic nervous system, was higher in the patients than in age-controlled normal volunteers both while supine and after standing. The plasma activity of dopamine-beta-hydroxylase, the enzyme that converts dopamine to NE, was significantly lower in the autistic patients and their healthy relatives than in control groups. Dopamine-beta-hydroxylase does not appear to provide an index of sympathetic activity in this group of patients who, on the basis of the elevated plasma levels of NE, may demonstrate a chronic state of hyperactivity of the sympathetic nervous system. Low enzyme activity found in both the autistic patients and their immediate families may be associated with this disorder.

Peripheral measures of serotonergic and noradrenergic function were obtained in 29 obsessive-compulsive adolescents and 31 age- and sex-matched controls, as well as in a subsample of 22 patients after five weeks of treatment with clomipramine hydrochloride (134 +/- 33 mg/d) (mean +/- SD) given in a double-blind placebo-controlled trial. Drug-free obsessive-compulsive subjects did not differ from controls on measures of platelet serotonin and monoamine oxidase (MAO) activity, nor on plasma epinephrine or norepinephrine concentrations at rest and after a standard orthostatic challenge procedure. Compared with placebo, treatment with clomipramine was clinically effective and produced a marked decrease in platelet serotonin concentration, a trend toward a reduction in platelet MAO activity, and a rise in standing plasma norepinephrine. Clinical improvement during drug therapy was closely correlated with pretreatment platelet serotonin concentration and MAO activity, as well as with the decrease in both measures during clomipramine administration. This suggests that the effects of clomipramine on serotonin uptake may be essential to the antiobsessional action observed.

Urinary monoamines and metabolites as well as plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol were measured in 14 boys (mean age, 9.2 years) with Attention Deficit Disorder With Hyperactivity during an initial placebo period, after four weeks of treatment with either dextroamphetamine sulfate (N=5) or a monoamine oxidase inhibitor (N=9) and at the end of a subsequent two-week placebo "washout" period. Both dextroamphetamine and monoamine oxidase inhibitors produced persistent changes in monoamines and metabolites, which were most marked and consistent for NE and its metabolite 3-methoxy-4-hydroxyphenylglycol. These changes did not correlate in a consistent fashion with clinical response during drug treatment. Moreover, there was rapid clinical relapse following cessation of either treatment while the alterations in NE metabolism remained during the two weeks following drug, further demonstrating the independence of these changes from clinical state. Future studies with dextroamphetamine need drug-free periods that are greater than 14 days to obtain true "baseline" conditions.

Previous reports have indicated that platelet monoamine oxidase (MAO) activity is reduced in patients with the bipolar form of major affective illness. We present evidence that platelet MAO activity is also significantly reduced in the first-degree relatives of bipolar patients. However, platelet MAO activity did not distinguish ill from well family members. It is possible that reduced platelet MAO may be an indicator of increased familial vulnerability to affective disorders.

Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with decreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.

Fourteen boys (mean age, 9.2 +/- 1.5 years) with Attention Deficit Disorder (ADD) With Hyperactivity were treated with dextroamphetamine sulfate or a monoamine oxidase inhibitor (MAOI) (six received clorgyline, eight received tranylcypromine sulfate) for four weeks each in a double-blind, cross-over study that included a two-week placebo washout between active drug periods. The MAOIs had immediate, clinically significant benefit and were clinically indistinguishable from dextroamphetamine. Most children responded to both stimulant and MAOI. These findings of equivalent efficacy of MAOIs in ADD are in contrast to our previous studies with neurotransmitter system selective agents, which showed only weak effects, and suggest that multiple neurotransmitter alterations may be required for stimulant drug effects in ADD. The immediate response to MAOIs indicates a different mechanism from that mediating antidepressant effect. The MAOIs may be useful alternate treatments in selected cases of ADD.

Clomipramine is a potent serotonin reuptake blocker that decreases the symptoms of obsessive-compulsive disorder (OCD). To investigate whether clomipramine treatment in OCD affects brain serotonergic responsiveness, metachlorophenylpiperazine (mCPP), a selective serotonin agonist, and placebo were given under double-blind conditions to nine patients with OCD before and after treatment with clomipramine. Unlike our previous observations of a marked transient increase in obsessional symptoms and anxiety following 0.5 mg/kg of mCPP, readministration of mCPP after four months of treatment with clomipramine did not significantly increase obsessional symptoms and anxiety. Similarly, the hyperthermic effect of mCPP observed before treatment was eliminated after treatment with clomipramine. These findings are consistent with the development of adaptive subsensitivity to the serotonergic agonist mCPP during clomipramine treatment. A similar alteration in the response to endogenous serotonin may mediate clomipramine's antiobsessional effects.

Patients with obsessive-compulsive disorder who met DSM-III criteria and who had been ill for at least one year were studied in a double-blind, randomized, crossover comparison of the tricyclic antidepressant clomipramine hydrochloride and the monoamine oxidase inhibitor clorgyline hydrochloride. No significant improvement was evident after four weeks of treatment with placebo prior to the crossover study. Treatment with clomipramine was associated with significant improvement after both four and six weeks in measures of obsessions, anxiety, and depression. Antiobsessional responses to clomipramine did not depend on presence of depression. Improvement was correlated with plasma concentrations of clomipramine, but not with the plasma concentrations of any of its metabolites. No significant improvement was evident for the entire group with clorgyline treatment, although the conditions of individual patients did respond to the drug.

Motor performance and cognitive function were examined in depressed patients and controls. Increasing severity of depression was strongly associated with decrements in performance in both motor and memory tasks. Greatest depression-related impairment was found on those cognitive and motor tasks that required sustained effort. We discuss these results in terms of a generalized deficit in the central motivational state of depressed individuals.

To examine the "serotonin hypothesis" of obsessive-compulsive disorder (OCD), we studied the behavioral and neuroendocrine effects of metachlorophenylpiperazine (mCPP), a serotonergic agonist, in patients with OCD and healthy controls. Twelve patients and 20 controls were given a single dose of 0.5 mg/kg of mCPP, administered orally under double-blind, placebo-controlled, random-assignment conditions. Following mCPP, but not following placebo, patients with OCD experienced a transient but marked exacerbation of obsessive-compulsive symptoms. Moreover, compared with healthy controls, patients exhibited greater other behavioral (but not endocrinologic or thermal) changes after mCPP. These findings are consistent with a special role for the neurotransmitter serotonin in OCD psychopathology.