Search

In a single-blind study chromosome analyses were performed on three groups of subjects: 1) nine heavy users of LSD-25 who have continued to use the drug; 2) eight heavy users of LSD-25 who have ceased to use it; and 3) eight drug-free control subjects. The results revealed no significant differences in chromosome break-age rates between any of the three groups and therefore no temporal factor was elicited regarding chromosome damage and LSD ingestion. The mean breakage rates for all three groups were 1.8 percent or less and did not support earlier findings that LSD ingestion causes an increase in chromosome aberrations over those observed in a normal control population. The authors emphasize the need for a more controlled longitudinal study.

The free clinic is a relatively new medical institution and few data exist on the kinds of populations it serves. The authors studied a group of patients who appeared at a free clinic in San Diego. They found that most of the patients were white and middle class in origin; that drug abuse was high but was not a common presenting problem; that the group was suspicious of the validity of information published in "Establishment" news media; and that hallucinogens would he more widely used if they were more available.

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. Language: en

Considerable evidence has accumulated indicating that alterations in neurotransmitters may play a role in the etiology of affective disorders on the one hand, and in the regulation of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) on the other. Acetylcholine, norepinephrine, serotonin, GABA, the opioid polypeptides and dopamine have all been implicated in both phenomena. Although some contradictory evidence exists, norepinephrine, opioids, and GABA appear inhibitory, and serotonin and acetylcholine appear excitatory of the LHPA axis. In a correlative study, non-suppression of cortisol by dexamethasone correlated positively and significantly with methylphenidate-induced euphoric and antidepressant responses, and methadone induced growth hormone responses, possibly suggesting catecholamine and opioid receptor hypersensitivity. Although the overall effects of the cholinomimetic, physostigmine, did not correlate with dexamethasone non-suppression, strong positive correlations were found in a subgroup, consisting of affective disorder patients, between non-suppression of cortisol by dexamethasone and the physostigmine response, suggesting cholinergic hypersensitivity in the non-suppressing subjects.

Intravenous methylphenidate (0.5 mg/kg) caused human serum growth hormone to be significantly increased following methylphenidate infusion, an effect attenuated in schizophrenics, as contrasted to non-psychotic patients, and in antipsychotic drug treated individuals. Serum prolactin levels significantly decreased from baseline after methylphenidate infusion.

In the previous chapter, the findings from the clinical studies conducted by our group at the University of California, San Diego, are described and commented upon. Davis et al. (1977) reported a decline in unusual thought content and Berger et al. (1977) noted a reduction in auditory hallucinations in schizophrenics following naloxone infusion. This short chapter will highlight the way in which animal work generated the human investigations and describe the overall conceptual framework which has guided our research in this area.

Converging lines of evidence from a variety of independent research studies suggest that affective disorder patients may be more reactive to centrally acting cholinomimetic agents. To explore this possibility, the current study compared the behavioral and neuroendocrine effects of the cholinesterase inhibitor, physostigmine salicylate (.022 mg/kg), in affective and non–affective disorder psychiatric patients. Affective disorder patients were found to have a relatively greater tendency to develop behavioral inhibition and anergia, negative affect and exaggerated prolactin responses following physostigmine infusion. No significant differences were found with respect to physostigmine-induced increases in pulse, blood pressure or serum cortisol. Thus, it is possible that exaggerated behavioral and prolactin responses to physostigmine may be markers of affective disorder.

The interaction between the reversible cholinesterase inhibitor, physostigmine, and lithium chloride was studied in adult male rats. A combination of lithium plus physostigmine increased lethality more than that caused by either physostigmine or lithium alone. Scopolamine completely reversed this effect. These drug interactions may have clinical significance, since lithium plus cholinesterase inhibitors may be used together in the practice of medicine.

• The responses of 24 normal male subjects were compared after two 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 judgment, and semantic creativity. This was a placebocontrolled, 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.

Extreme and debilitating fluctuations in mood have long been thought to involve chemical imbalances in the central nervous system. The role of catecholamines in the affective disorders has been emphasized since the pioneering work by Schildkraut and Kety (1967) and others, who noted that drugs which elevate mood and which are effective in the treatment of depression facilitate catecholaminergic transmission in the brain, and conversely, that drugs which may produce depression and that are used in the treatment of manic behavior tend to antagonize the synaptic actions of dopamine and norepinephrine. Measurements of catecholamine metabolites in the urine and cerebrospinal fluid of manic and depressed patients have also produced some evidence consistent with the view that depression is associated with reduced catecholaminergic synaptic transmission (Schildkraut, 1973; Schildkraut and Kety, 1967).

Oral methylphenidate (1.0 mg/kg) and intravenous methylphenidate (0.5 mg/kg) were compared as to their ability to increase behavioral activation, pulse, blood pressure, and serum growth hormone. Intravenous methylphenidate was considerably more effective than oral methylphenidate in activating behavior and in increasing pulse and blood pressure. Although oral methylphenidate appeared to increase behavioral activation, this effect was not statistically significant.

Despite the extremely widespread use of antipsychotic medications, there is little evidence from the surveys conducted to date, that this class of psychoactive medications is significantly implicated in vehicular crashes or deaths. In five major surveys of vehicular fatalities, in which drug and alcohol analyses were obtained, only two of over 800 victims studied involved detection of antipsychotic medications. It is clear that the acute administration of antipsychotics in normal individuals does induce sedation and performance decrements in visual-motor coordination and specific attentional behaviors, which have a deleterious effect on driving behavior. On the other hand, it should be emphasized that antipsychotics are rarely used on an acute basis and tolerance to the sedation and decreased alertness does occur during chronic treatment. Antipsychotic drugs have the capacity to potentiate the effects of alcohol, sedative hypnotics, narcotics and antihistamines; therefore, the combination of antipsychotics with these substances increases the impairment of driving behavior. There is an indication that the less sedating piperazine phenothiazines and the butyrophenones may have little or no effect on psychomotor performance, and antipsychotic drugs of these two subclasses may have a distinct advantage, at least in terms of driving performance, over the other more sedating drugs. Antipsychotic drugs are almost never used for recreational or abuse purposes; therefore, more central to the focus of this review is the effect that antipsychotics may have on the driving behavior of those seriously disordered mentally ill patients who require continued maintenance on these medications. There is good agreement in the literature which suggests that schizophrenic patients demonstrate improved psychomotor performance during chronic treatment with antipsychotic drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Physostigmine, a centrally acting cholinesterase inhibitor, antagonizes methylphenidate-induced stereotyped gnawing behavior in mice and rats. This effect is significantly attenuated when lithium chloride is concurrently administered, indicating that lithium chloride may antagonize central cholinergic activity. This observation may have theoretical implications for an adrenergic-cholinergic balance hypothesis of affective disorders.

— Actively psychotic schizophrenic and nonpsychotic psychiatric inpatients received intravenous methylphenidate hydrochloride (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.

• 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 the personality inventories.

Methylphenidate (0.5 mg/kg) and placebo were administered intravenously to twenty psychiatric inpatients. Subjects engaged in one-hour dialogues with trained interviewers after infusion. The typical methylphenidate effects on mood and psychopathology were observed. Subjects also reported increases in their perception of regard from their interviewers. The prediction, concomitants, and implication of drug-induced changes in interpersonal perceptions are discussed.

Endogenous and exogenous opiate-like compounds have been found to cause increased serum growth hormone and prolactin levels in animals, and, in some cases, humans. Naloxone, a relatively specific narcotic antagonist, decreases serum prolactin and growth hormone levels in animals. Naloxone (20 mg IV) did not significantly alter serum prolactin levels and, minimally but not significantly, increased growth hormone levels in humans to whom it was administered.

A wide variety of neuroendocrine abnormalities have been reported in affective disorder patients. Probably the most extensively studied have been hypothalamic-pituitary-adrenal (HPA) activation and dexamethasone resistance. In addition, an elevated 24-h pituitary growth hormone secretion has been reported in depressed patients. Reduced pituitary growth hormone responses to central nervous system (CNS) probes have been reported in depressed patients, particularly in response to the noradrenergic agent clonidine. The sequencing and availability of corticotropin-releasing factor (CRF) and growth hormone-releasing factor (GRF) allow direct testing of pituitary responses to these neuropeptides in affective disorder patients. Our findings to date confirm the reports by Gold and colleagues1 and Holsboer and colleagues2 of an attenuated ACTH response to intravenously administered ovine CRF in depressed patients. In addition, we preliminarily report an attenuated growth hormone response to intravenous human GRF in depressed patients.

In a preliminary, prospective pilot study, five patients with major depressive disorder and eleven age and sex matched normal controls received intravenous human growth hormone releasing factor (hGRF) (1 μg/kg in 5 cc of normal saline infused over five minutes) and placebo. Thirty minutes after insertion of the catheter, blood was sampled every 15 minutes for thirty minutes prior to and for 2 hours subsequent to intravenous infusion of hGRF or placebo. hGRF but not placebo caused significant elevations of plasma growth hormone levels in all subjects. Of interest, the depressed patients had a significantly attenuated rise in plasma growth hormone concentrations when compared with the normal controls. These results must be considered preliminary awaiting replication with a larger subject population.

Heroin use histories and related institutional involvements were obtained from 30 female heroin addicts. Presence of intimate (vs casual) companions at first heroin use strongly differentiated subsequent high vs low consumption patterns. Intimate others were precipitants in 60% of all treatment episodes; the duration of such episodes was nearly double that for self-precipitated admissions. Concurrent familial determinants were indicated in virtually all accounts of current consumption patterns. It is concluded that romantic/kinship units and liaisons of female addicts are an important focus for research, policy, and therapeutic interest.

Unrecognized, untreated, and undertreated depressive disorders extract an inordinate human and economic cost, despite the availability of an extensive array of effective clinical interventions. To enhance the availability and quality of care, the National Institute of Mental Health launched the Depression Awareness, Recognition, and Treatment Program, a multiphase information and education program designed to alert health professionals and the general public to the fact that depressive disorders are common, serious, and treatable. The authors review the development of this program, describing the professional education efforts it supports in anticipation of increased demand for services, the public education campaign launched in May 1988, and highlights of the scientific advances that make the program feasible and timely.

• 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.

In a double-blind, crossover design, 10 mg of methadone or an inert placebo were administered intramuscularly to nine acutely manic patients in identical experimental sessions separated by 1 day. Standardized behavioral observations, self-ratings of mood and affect, and blood samples for prolactin and cortisol were obtained at baseline and 30, 60, and 120 minutes after the administration of methadone or placebo. Methadone decreased symptoms of euphoria, elation, and grandiosity in these manics. There was a significant rise in prolactin, peaking at 60 minutes, and a significant decrease in cortisol, maximal at 120 minutes following methadone administration. There appeared to be a correlational consistency between the subduing effects of methadone on behavior and its effect upon prolactin and cortisol secretion. These findings, together with data from previous studies of our own and others, suggest that a potentially important interrelationship may exist between the central endogenous opioid peptide systems, various neuroendocrine regulatory factors, and the pathophysiology of affective disorder.

Since 1977, we in the Department of Psychiatry of the University of California at San Diego have been exploring the possibility that the endogenous opioids play a role in the etiology of the major psychiatric disorders. We have employed neuroendocrine and behavioral measures to evaluate the effects of the narcotic antagonist naloxone and the opiate agonist methadone and have studied normal controls and patients with schizophrenia and affective disorders.

Considerable attention has focused recently on the possibility that endogenous peptides with opioid-like activity (endorphins) may have a role in the regulation of normal and abnormal human behavior. Animal studies support the possibility that endorphins may have behavioral effects, apart from their known analgesic properties. Bloom et al. (1976) and Segal et al. (1977) noted that centrally administered s-endorphin induces rigidity and immobility in rats, and Bloom et al. (1976) noted that i.v.t. s-endorphin induces a ‘catatonic-like state, reminiscent of some aspects of schizophrenia, reversible with the relatively pure narcotic antagonist naloxone’. In addition, naloxone has been reported to inhibit apomorphine-induced stereotyped behavior in the rat (Cox et al. 1976); to enhance chlorpromazine’s effects on schedule-controlled behavior in pigeons (McMillan, 1971); to inhibit d-amphetamine-induced increases in locomotor activity (Holtzman, 1974; Segal et al. this volume) and continuous avoidance responding in rats (Holtzman, 1974); and to reverse the effect of morphine and d-amphetamine on intracranial self-stimulation in rats (Holtzman, 1974).

It has been proposed that affective disorders may be regulated by a complex balance between adrenergic and cholinergic factors, with depression being a disease of cholinergic predominance and mania being the converse (Janowsky et al., 1972a). As reviewed elsewhere (Janowsky et al., 1972a), much psychopharmacologic information supports this possibility, including the observation that effective antidepressant treatments such as the tricyclic antidepressants and ECT generally increase adrenergic activity and decrease cholinergic activity. Conversely, two effective antimanic agents, reserpine and haloperidol, increase cholinergic activity, and drugs which cause depression, such as reserpine and propranolol, have cholinergic, as well as antiadrenergic properties.

Visual cortical evoked potentials (EPs) have been employed in examining many Psychopathologic and neurologic states in man: assessing intellectual levels of functioning, assessing hemispheric specialization of function, and assessing drug effect, not to mention the enormous quantity of work accomplished in the basic sciences with single-cell and ganglion preparations. A clinical area of interest is application of EPs in Psychopathologic states.

In a double-blind design, length of hospital stay, changes in psychiatric symptoms, ward behavior, and posthospitalization treatment recommendations were examined as a function of good or poor premorbid status and medication or placebo treatment in a sample of men with acute schizophrenia. There were few initial differences in psychiatric symptoms or in ward functioning between the premorbid groups. Nevertheless, the good premorbid patients showed more rapid remission of symptoms and, hence, earlier discharge. Of the patients who were discharged early, more of the good premorbid patients fell in the placebo group in sharp contrast to the discharged poor premorbid patients, who were predominantly in the medication group. This trend toward more rapid improvement among patients with a good premorbid history in the absence of phenothiazines was supported by data indicating they required less posthospitalization medication.

FOR the purposes of this paper the symptoms of obsession and compulsion will be defined and identified separately. The term obsession will refer to an unwanted repetitive thought, which insistently forces itself into consciousness and recurs against the wishes of the patient. It may include ideas, images, affects, or impulses, which neither reason, logic, nor conscious effort are able to influence. A compulsion has many qualities in common with an obsession, but it is expressed in action and is described as a repetitive, stereotyped, and often trivial motor act. Failure to perform the compulsive act results in increasing anxiety, but once performed there is usually a temporary subjective reduction of tension. The essential nature of the obsessive compulsive symptoms, as opposed to similar personality traits, is that they are recognized by the patient as being incongruous and alien to his personality and

Thematic Apperception Test (TAT) stories of 24 sets of families containing disturbed adolescents were analyzed according to: 1) perceptual cognitive structuring of cards; and 2) quality of interpersonal relationships described. The cards used had a high probability of stimulating familial themes.Fou

The paper presents evidence concerning the stability and sensitivity of three classes of behavioral measures: a) word association quality, b) perceptual coping style, and c) skin resistance level and reactivity across a 21-day interval. Acute schizophrenic males were administered these measures 7 and 28 days following admission to a State hospital. Half of the patients were assigned to active phenothiazine medication at 7 days and half continued on placebo.

The diuresis induced by chlorothiazide (Diuril) was studied in 15 patients hospitalized for toxemia of pregnancy, 100 women whose pregnancies were progressing normally, except for varying degrees of pitting edema of the legs, and 35 additional patients in whom the edema, being complicated by hypertension with or without proteinuria, led to the diagnosis of toxemia of pregnancy. Doses of 500 mg., one to four times daily, resulted in striking increase in the urinary excretion of sodium and chloride ions and of water, with corresponding loss of body weight. Potassium excretion was also increased, but not so strikingly, and the excretion of ammonia and titratable acids was less significantly affected. The intravenous administration of 5 to 10 mg. of chlorothiazide per kilogram of body weight caused similar diuresis beginning within 20 minutes after the injection, without any significant effect on blood pressure and pulse rate. The data showed that chlorothiazide can be used with satisfactory results and with minimal side-effects in the treatment of edema of pregnancy.

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.

Volavka and Jacquet raise some issues of interest. It is true that at the inception of our studies the working hypothesis was that an excess or deficiency in opiate receptor activity might be responsible for mania and depression, respectively. This hypothesis was helpful in the beginning, but it has proved to be much too simplistic to effectively explain the potential role the opioid peptides may play in the pathophysiology of affective disorder. Therefore, we have abandoned this hypothesis. As Volavka and Jacquet point out, were the original hypothesis to be correct, naloxone hydrochloride should accentuate depression and exogenous opiates or opioids should exacerbate mania. We have preliminary data that have bearing on this issue. We have studied eight acutely manic patients who were administered 10 mg of methadone hydrochloride intramuscularly in a crossover, double-blind study. Systematic observations of the patients' behavior before and after placebo or methadone administration revealed a

• A controlled three-month prospective collaborative investigation involving eight National Institute on Drug Abusesupported polydrug units was carried out. Clinical review of test protocols assessed 37% of polydrug users, 26% of psychiatric patients, and 8% of nonpatients as impaired on the Halstead-Reitan Battery. Impairment in test performance was related to increasing age, educational deprivation, and premorbid medical factors in all groups, extensive use of CNS depressants and opiates among polydrug users, and extensive use of antipsychotic drugs in psychiatric patients. Both language-related and perceptuomotor neuropsychological test deficits were found in polydrug users, but only the latter in psychiatric patients. At three-month follow-up 34% of polydrug users, 27% of psychiatric patients, and 4% of nonpatients were impaired in these test performances. Recent drug-taking (polydrug group) and schizophrenia diagnosis (psychiatric patients) were additional correlates of test impairment. Persistence of performance deficit in polydrug users raises the possibility that CNS depressants and opiates may have longer-term, slowly reversible, or even permanent effects on neuropsychological tests. The same possibility exists for antipsychotic drugs. The link of these test deficits to other specific neuropsychological functions, to performance in life situations generally, or to specific brain dysfunction, as well as the basis for a lack of test impairments in the majority of polydrug subjects remain to be determined.

• 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.