Methylphenidate hydrochloride effects on psychological tests in acute schizophrenic and nonpsychotic patients.

Actively psychotic schizophrenic and nonpsychotic psychiatric inpatients received intravenous methylphenidate hydrochlroide (0.5 mg/kg). Each patient was rated for level of psychosis and talkativeness, and each received the Holtzman projective ink blot tests and the Kent-Rosanoff word-association tests before, during, and after methylphenidate infusion. Minnesota Multiphasic Personality Inventory Goldberg Index scores were also obtained as a general measure of psychosis. For the entire patient group, methylphenidate infusion was followed by a significant increase in talkativeness and psychosis ratings and in pathological responses to the Holtzman ink blot test. There was a significant decrease in common word associations. Since neither of the psychological tests allow more than one response per item, it appears that methylphenidate truly effects pathological thought processes and decreases common word associations as such, rather than merely making these processes more evident by increasing verbalization.

Naloxone-induced behavioral and physiological effects in normal and manic subjects.

Intravenous naloxone hydrochloride (20 mg) was administered to eight normal control subjects and 12 affective disorder patients manifesting manic or hypomanic symptoms. On two consecutive days, in a counterbalanced order, naloxone and placebo were given in a double-blind crossover design. The overall effect of naloxone was to decrease pulse rate and to promote lethargy and inactivation. The normal controls manifested reduced feelings of well-being, and the manic patients noted a subjective sense of slowing. There was a variable response pattern to naloxone in the manic patients in which four of the 12 patients manifested an observable reduction in their manic symptoms and behavior after the naloxone administration. Naloxone seems to have had a nonspecific subduing effect in both normal subjects and patients and may also have had a selectively greater effect in a small subsample of the manics.

Interpersonal effects of marijuana. A model for the study of interpersonal psychopharmacology.

The effect of marijuana on affective changes and interpersonal skills, including empathy, acceptance, warmth, and genuineness, was studied in 20 dyadic relationships in which the experimental subject smoking marijuana containing 6 mg of delta-9-tetrahydrocannabinol and a placebo in separate trials. Marijuana caused a relative decrease in the ratings of the interpersonal skills of the experimental subjects and decreased affective resonance between the experimental subjects and their partners.

The effect of lithium carbonate on affect, mood, and personality of normal subjects.

Data reflecting affect, mood, and personality attributes of 23 normal men were compared after two weeks of placebo administration and two weeks of therapeutic serum lithium levels (mean, 0.91 mEq/liter). The study was a placebo-controlled, split-half crossover, double-blind design. Affect and mood were measured by three self-rating instruments, independent rater observation, and by the subjects' "significant others." Two personality inventories were administered. Substantial affect and mood changes are induced by lithium carbonate. Lethargy, dysphoria, a loss of interest in interacting with others and the environment, and a state of increased mental confusion were reported. No generalized effects were found in the responses to ther personality inventories.

The effect of lithium carbonate on the cognitive functions of normal subjects.

The responses of 24 normal male subjects were compared after weeks of placebo administration and two weeks of lithium carbonate administration (mean serum lithium level, 0.9 mEq/liter) on a series of tasks of intellectual function, aesthetic judgement, and semantic creativity. This was a placebo-controlled, split-half crossover, double-blind design. There were no significant changes on semantic creativity or aesthetic perception measures following lithium carbonate maintenance. There were lithium carbonate-related performance deficits on three of five performance tasks concerned with cognitive and/or motor functions. The deficit is probably due to a lithium carbonate-induced slowing of performance, consistent with our previous report of subjective effects in normal subjects. The implications of slowing on possible behavioral mediating mechanisms by which lithium carbonate exerts its clinical effects are discussed.

Blunted prolactin response. A neuroendocrine abnormality manifested by depressed patients.

Prolactin concentrations of 30 unmedicated psychiatric inpatients and 11 normal controls were measured at baseline and at 30 and 60 minutes after the administration of 10 mg of intramuscular methadone hydrochloride. Methadone raised the prolactin level at 60 minutes to more than twice the mean baseline level for the full subject sample. Patients with depressive disorders had lower mean basal prolactin levels than did the other subjects, and also manifested attenuated prolactin responses to methadone. Eight of 16 depressives had markedly blunted prolactin responses, a finding consistent with other studies reporting deficient responses in depression. These data are consistent with the hypothesis that the pathophysiology of depressive disorders involves dysfunctions in the anterior pituitary itself or in the hypothalamic neurotransmitter and neuromodulator systems (eg, endorphins) that regulate the secretion of prolactin and other neurohormones.

Lithium carbonate and ethanol induced "highs" in normal subjects.

The responses of twenty-three normal male subjects to a standardized dose of 95% ethanol (1.32 ml/kg of body weight) were compared after two weeks of placebo and two weeks of therapeutic serum lithium ion levels (mean 0.91 mEq/liter). The study was a placebo controlled, split-half crossover, double-blind design. Prealcohol and postalcohol responses were assessed by self-rating scales of affect and mood, independent rater observation, perceptual-motor, and cognitive performance tasks. Pretreatment by lithium carbonate neither blocked nor dampened an alcohol-induced subjective "high" in normal subjects. A complex reciprocal interaction may exist between the effects of lithium and alcohol upon other behavioral attributes. Alcohol was seen to reverse aspects of lithium-induced dysphoria and there is a suggestion that lithium may attenuate alcohol-induced cognitive inefficiency.

A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.

BACKGROUND: Investigations of unipolar major depressive disorder (MDD) have focused primarily on major depressive episode remission/recovery and relapse/recurrence. This is the first prospective, naturalistic, long-term study of the weekly symptomatic course of MDD. METHODS: The weekly depressive symptoms of 431 patients with MDD seeking treatment at 5 academic centers were divided into 4 levels of severity: (1) depressive symptoms at the threshold for MDD; (2) depressive symptoms at the threshold for minor depressive or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs), below the thresholds for MinD and MDD; and (4) no depressive symptoms. The percentage of weeks at each level, number of changes in symptom level, and medication status were analyzed overall and for 3 subgroups defined by mood disorder history. RESULTS: Patients were symptomatically ill in 59% of weeks. Symptom levels changed frequently (1.8/y), and 9 of 10 patients spent weeks at 3 or 4 different levels during follow-up. The MinD (27%) and SSD (17%) symptom levels were more common than the MDD (15%) symptom level. Patients with double depression and recurrent depression had more chronic symptoms than patients with their first lifetime major depressive episode (72% and 65%, respectively, vs 46% of follow-up weeks). CONCLUSION: The long-term weekly course of unipolar MDD is dominated by prolonged symptomatic chronicity. Combined MinD and SSD level symptoms were about 3 times more common (43%) than MDD level symptoms (15%). The symptomatic course is dynamic and changeable, and MDD, MinD, and SSD symptom levels commonly alternate over time in the same patients as a symptomatic continuum of illness activity of a single clinical disease.

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

Historical highlights of the National Institute of Mental Health from 1946 to the present.

This introduction briefly highlights NIMH's history from its inception until today. It is not meant as, nor could it be, a detailed history of NIMH but is offered primarily as a perspective by which to read the articles in this supplement. Obviously, the history of any institution is the personal history of its leadership, and contained in this special issue are the personal reminiscences of six of the eight Directors of NIMH, who review their tenures at the Institute from the perspective of the central contributions and advances made by NIMH during the time they served as Director. As such, it is an interesting and informative personalized history of one of the world's great institutions and one that has played and continues to play a central and vital role in this nation's response to its mentally ill citizens.

NIMH during the tenure of Director Lewis L. Judd, M.D. (1987-1990): the decade of the brain and the four national research plans.

My tenure at NIMH was an exhilarating, heady time of great satisfaction and achievement for all of us at the Institute. I have great affection and loyalty for NIMH, but my fondest memories are of the individuals who led and staffed the Institute's programs while I was there. One of the most gratifying aspects of my tenure was the opportunity to recruit and appoint people to new responsibilities and to interact with and support them as they grew into and beyond their positions of leadership within NIMH. When I left NIMH, I felt that the Institute's managers and staff were unparalleled in their creativity, competence, commitment, loyalty, and sheer hard work on behalf of the Institute and our field. My thanks and deep gratitude genuinely go out to the entire staff at NIMH during my tenure. However, a special debt of gratitude is owed to a group of colleagues and friends who, at my request, carried very heavy responsibilities and excelled in meeting them: Dr. Alan Leshner (Deputy Director of NIMH, now Director of NIDA); Dr. Stephen Koslow, Dr. Stephen Paul, Dr. Jack "Jay" Burke, Dr. David Segal, Dr. Ira Glick, Dr. Ellen Stover, Dr. Irene Levine, Dr. Daryl Kirsch, Dr. Rex Cowdry, Dr. Sam Keith, Dr. Delores Paron, Leroy Goldman, Richard Pine, William Fitzsimmons, Gordon Seidenberg, Lewis Steinberg, Gemma Weiblinger, George Halter, and my invaluable assistant, Margaret Shanley.

Neuropsychological and EEG disturbances in polydrug users.

EEG and neuropsychological evaluation of 66 polydrug users revealed that 43% had EEG abnormalities and 45% had neuropsychological impairment 3 weeks after admission to a polydrug study unit. At 5-month follow-up, 27% of 30 retested subjects were still impaired neuropsychologically. Impairment may be related to extensive involvement with sedatives, alcohol, or heavy polydrug use. The authors suggest that cerebral dysfunction in polydrug users might be the result of organicity of intermediate duration and that deficits may be experienced by some beyond 5 months of reduced use or abstinence. Organicity may dictate structured, reality-based intervention techniques, especially early in treatment.

Lithium antagonizes ethanol intoxication in alcoholics.

Thirty-five detoxified alcoholics given lithium in a placebo-controlled, double-blind study reported less intoxication, a decrease in the desire to continue drinking, and less cognitive dysfunction when challenged by standardized doses of ethanol. Lithium also appeared to antagonize the ethanol-induced decrement in cognitive and perceptual motor performance. No differential lithium effect was noted when alcoholics were divided by diagnoses of affective disorder versus no affective disorder. The authors suggest that, in addition to mood normalization, lithium's capacity to directly affect ethanol intoxication may help explain its potential therapeutic efficacy in alcoholism, providing further confirmatory evidence that lithium may be useful in the treatment of alcoholism.

Functioning and well-being of patients with panic disorder.

OBJECTIVE: The authors compared the health-related quality of life of patients with panic disorder to that of patients with other major chronic medical and psychiatric conditions. METHOD: The physical and mental health of a group of 433 patients with current panic disorder and 9,839 outpatients with psychiatric or medical disorders were assessed with the 20- and 36-item short-form surveys of the Medical Outcomes Study. After controlling for other disease conditions, demographics, and study site, the authors used multiple regression methods to estimate health-related quality of life levels for panic disorder patients and patients with hypertension, diabetes, heart disease, arthritis, chronic lung problems, and major depression. RESULTS: Patients with panic disorder had levels of mental health and role functioning that were substantially lower than those of patients with other major chronic medical illnesses but were higher than or comparable to those of patients with depression. However, their physical functioning levels and perceptions of current health were more like those of patients with hypertension and were similar to general population norms. CONCLUSIONS: Panic disorder is a serious societal health problem with large consequences, and it affects primarily psychological and role domains.

Sensory gating deficits in schizophrenia: new results.

OBJECTIVE: It has been widely hypothesized that sensory gating failures and sensory overload occur in schizophrenic patients compared to normal subjects. The authors of this study sought to confirm and extend results of earlier studies that showed specific sensory gating deficits in schizophrenic patients. METHOD: Age- and sex-matched schizophrenic patients (N = 20) and normal subjects (N = 20) were tested using electrophysiologically recorded P50 event-related potentials to assess the overall competence of the subjects' central sensory inhibitory capacity by measuring sensory filtering or gating. P50 area responses to two 75-dB (conditioning and test) click stimuli of 0.04-msec duration, averaged over 60 trials, were recorded for each subject. Normally, the first (conditioning) click stimulus induces gating mechanisms that result in diminished or gated P50 event-related potentials in response to the second click stimulus. RESULTS: The schizophrenic subjects manifested a significant sensory gating deficit at frontal, central, and parietal electrode placement sites, with a nonsignificant tendency for the deficit to be most prominent in the frontal areas of the brain. CONCLUSIONS: These data reflect a regionally diffuse loss of normal sensory gating in schizophrenic patients.

Effects of lithium carbonate on memory and other cognitive functions.

The authors studied the effects of lithium carbonate on memory and cognitive function in 16 psychiatric patients, who received lithium for 2 weeks and placebo for 2 weeks in a double-blind cross-over design. At the end of each treatment phase, subjects were administered a battery of memory and cognitive tests. As reported previously, lithium induced slowing of performance on certain of the perceptual motor tests; however, lithium did not cause memory impairment or a change in self-assessment of memory functions.

Opiate addiction and suicidal behaviors.

The authors tested the hypothesis that people addicted to opiates manifest more psychopathology in areas that have been identified as predictors for high risk of suicidal behavior than do normal control subjects. They gave 278 patients in a methadone maintenance program and 207 normal control subjects the index of Potential Suicide (IPS), a scale designed to assess suicidal risk. Using discriminate function analysis, the authors found that 87% of 100 of the methadone patients and 98% of 100 of the normal control subjects were correctly identified on the basis of the IPS data.

Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population.

OBJECTIVE: The authors' goal was to evaluate the association between impairment in daily function and subsyndromal depressive symptoms as well as major depression to determine the economic and societal significance of these conditions. METHOD: Using 12-month prevalence data gathered by the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program (ECA), based on responses to the NIMH Diagnostic Interview Schedule, the authors divided the 2,393 subjects from the Los Angeles ECA site into three groups: subjects with subsyndromal depressive symptoms (N = 270), major depression (N = 102), and no depressive disorder or symptoms (N = 2,021). The groups were compared on 10 domains of functional outcome and well-being. RESULTS: Significantly more subjects with depressive symptoms than subjects who had no disorder reported high levels of household strain, social irritability, and financial strain as well as limitations in physical or job functioning, restricted activity days, bed days, and poor health status. Significantly more subjects with major depression than subjects with no disorder reported major financial losses, bed days, high levels of financial strain, limitations in physical or job functioning, and poor health status. Except for lower self-ratings of health status, no significant differences were found between subjects with subsyndromal symptoms and those with major depression. CONCLUSIONS: Significantly more people with subsyndromal depressive symptoms or major depression reported impairment in eight of 10 functional domains than did subjects with no disorder. The high 1-year prevalence of subsyndromal depressive symptoms, combined with the associated functional impairment, emphasizes the clinical and public health importance and need for additional investigations into these symptoms.

Organic impairment in polydrug users: risk factors.

In a national collaborative study to assess the neuropsychological status of 151 polydrug users, the Halstead-Reitan Neuropsychological Battery showed deficits in 37% two to three weeks after they entered treatment and in 34% at three-month follow-up. Comparative rates for a group of psychiatric patients were 26% and 27%, and for nonpatients, 8% and 4%. Extensive and intensive use of CNS depressants and opiates correlated positively with neuropsychological deficit. Older, less-educated subjects with adverse medical or developmental histories were more likely to show polydrug-related organic impairment. Although there is some evidence that such impairment is reversible, the condition appears to be of at least intermediate duration and may be long lasting.

Subthreshold depression and depressive disorder: clinical characteristics of general medical and mental health specialty outpatients.

OBJECTIVE: The authors examined the clinical significance of depressive symptoms below the threshold for depressive disorder in outpatient samples. METHOD: The subjects were 775 adult patients with current depressive disorder, 1,420 patients with subthreshold depression, and 1,767 hypertensive patients with and without depression, all of whom were visiting the offices of mental health specialists and general medical care providers in three U.S. cities. Data on demographic characteristics, severity of depression, extent of psychiatric and medical comorbidity, family psychiatric history, and treatment history for the patients with depressive disorder and those with subthreshold depression were compared. RESULTS: The percentage of patients with subthreshold depression who had a family history of depression (41%) was nearly as high as that of the patients with depressive disorder (59%). The two groups of patients had similar levels of medical and psychiatric comorbidity except for anxiety disorders, which were greater among the patients with depressive disorder. Among the hypertensive patients in the general medical sector, those with subthreshold depression were more similar to those with depressive disorder than to the nondepressed hypertensive patients. Treatment rates were considerably lower for patients with subthreshold depression than for patients with depressive disorder in the general medical sector, but they were similar in the mental health specialty sector. CONCLUSIONS: In these outpatients, subthreshold depression appeared to be a variant of affective disorder and was treated as such in the mental health specialty sector but not in the general medical sector. The findings emphasize the importance of treatment outcome studies of patients with subthreshold depression.