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After initial interviews with 20,291 adults in the National Institute of Mental Health Epidemiologic Catchment Area Program, we estimated prospective 1-year prevalence and service use rates of mental and addictive disorders in the US population. An annual prevalence rate of 28.1% was found for these disorders, composed of a 1-month point prevalence of 15.7% (at wave 1) and a 1-year incidence of new or recurrent disorders identified in 12.3% of the population at wave 2. During the 1-year follow-up period, 6.6% of the total sample developed one or more new disorders after being assessed as having no previous lifetime diagnosis at wave 1. An additional 5.7% of the population, with a history of some previous disorder at wave 1, had an acute relapse or suffered from a new disorder in 1 year. Irrespective of diagnosis, 14.7% of the US population in 1 year reported use of services in one or more component sectors of the de facto US mental and addictive service system. With some overlap between sectors, specialists in mental and addictive disorders provided treatment to 5.9% of the US population, 6.4% sought such services from general medical physicians, 3.0% sought these services from other human service professionals, and 4.1% turned to the voluntary support sector for such care. Of those persons with any disorder, only 28.5% (8.0 per 100 population) sought mental health/addictive services. Persons with specific disorders varied in the proportion who used services, from a high of more than 60% for somatization, schizophrenia, and bipolar disorders to a low of less than 25% for addictive disorders and severe cognitive impairment. Applications of these descriptive data to US health care system reform options are considered in the context of other variables that will determine national health policy.

Bipolar patients taking lithium carbonate were classified as rapid-cycling or non-rapid-cycling based on whether they had ever experienced four or more affective episodes in a 12-month period. Overt hypothyroidism was found in 12 (50.7%) of the 24 rapid-cycling patients and in none of the 19 non-rapid-cycling patients. Elevated thyroid-stimulating hormone levels were present in 92% of the rapid-cycling group v 32% of the non-rapid-cycling group. Abnormalities of the hypothalamic-pituitary-thyroid axis, some of which may become apparent only during treatment with lithium carbonate, appear to interact with a predisposition to bipolar illness to produce rapid-cycling. These overt and covert abnormalities may help explain the reported efficacy of thyroid in treating "periodic catatonia" and rapid-cycling.

We studied group and subgroup differences in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with major affective disorder (66 depressed, 13 manic) and normal volunteers (27 subjects). Bipolar I depressed patients excreted less MHPG than unipolar depressed patients, manic patients, or normal volunteers. The mean (+/- SEM) MHPG excretion rate was 1.44 +/- 0.10 mg/day in 19 depressed bipolar I patients, 1.79 +/- 0.11 mg/day in 28 unipolar depressed patients, 2.11 +/- 0.19 mg/day in 13 manic patients, and 1.85 +/- 0.12 mg/day in 27 normal volunteers. Other sources of variance that affected urinary MHPG levels did not explain subgroup or state differences. There was only a trend for a low pretreatment MHPG level to be associated with positive response to imipramine hydrochloride or desipramine hydrochloride in the 19 patients treated with these drugs. The application of this biological test value for prediction of differential response to antidepressant drugs would therefore seem premature.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 32 subjects. Those individuals with a low level of DBH in the CSF had significantly elevated profiles on the Minnesota Multiphasic Personality Inventory, suggesting a relationship between the central noradrenergic system and some aspects of personality in man.

Fifty-eight violent offenders and impulsive fire setters were followed up for an average of 3 years after release from prison. Recidivists who committed a new violent offense or arson had significantly lower cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid concentrations and blood glucose nadirs after oral glucose challenge than did nonrecidivists. A discriminant analysis, based on the blood glucose nadir and cerebrospinal fluid 5-hydroxyindoleacetic acid concentration, correctly classified 84.2% of the subjects.

The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.

In a double-blind study of depressed patients treated with imipramine hydrochloride, levels of imipramine and desipramine were measured in plasma and in CSF. Levels of both drugs in CSF were approximately 10% of plasma levels, but the levels in the two body fluids were highly correlated. The levels of both drugs were approximately equal in plasma, but desipramine predominated in CSF (imipramine/desipramine ratio of 0.8). The imipramine-induced alteration in CSF levels of the serotonin metabolite (5-hydroxy-indoleacetic acid [5HIAA]) correlated with imipramine levels but not with desipramine. For the group of patients showing a clear antidepressant response, the mean drug levels were nearly double those of the nonresponder group, a difference that did not quite reach statistical significance in this relatively small sample. The desipramine levels showed no responder-nonresponder difference, while the ratio of imipramine/desipramine was significantly higher among the responders. On the average this particular patient group had relatively low pretreatment levels of 5HIAA in CSF, an observation that may partially account for the relatively low overall response rate to imipramine.

Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in gamma-aminobutyric acid (GABA)-containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.

Wrist motor activity and sleep were monitored longitudinally in 15 rapidly cycling and 52 nonrapidly cycling manic-depressive patients. The majority of patients experienced one or more consecutive 48-hour sleep-wake cycles (alternate nights with no sleep) when they switched out of depression into mania of hypomania. During a depressive phase, nine rapidly cycling patients were asked to simulate a 48-hour sleep-wake cycle by remaining awake for 40 hours (one night's total sleep deprivation). Eight switched out of depression, and seven were rated as manic or hypomanic; indicating that sleep loss (such as occurs with spontaneous 48-hour sleep-wake cycles) may help to trigger switches from depression to mania. The 48-hour sleep-wake cycles in patients may depend on a mechanism that is normally present in all humans, since normal persons also spontaneously experience near-48 hour sleep-wake cycles in certain experimental conditions.

Twenty-four-hour (circadian) rhythms in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, motor activity, and oral temperature were studied in 14 normal subjects and ten manic-depressive patients. In both groups, a daily rhythm in MHPG excretion was present, with daytime peaks and nighttime lows. This pattern of urinary MHPG excretion may reflect a rhythm in central noradrenergic function. The physiological changes in levels of MHPG excretion associated with the circadian rhythm were at least as great as pathological changes associated with manic-depressive illness. Compared with controls, the timing or phase of circadian rhythms in each variable was one to three hours earlier in the patients, whether depressed or manic. Although the presence of circadian rhythms complicates the task of designing clinical research procedures, their early timing in manic-depressives suggests that disturbances in central biological clocks may be an integral part of the pathophysiology of affective illness and may be related to disturbances of sleep and neuroendocrine function associated with depression.

Red blood cell Na+, K+-, Mg2+-, and Ca2+-adenosine triphosphatase (ATPase) activities were studied longitudinally in eight patients with affective disorders and 12 healthy volunteers. The patients had a higher mean Ca2+-ATPase activity than the volunteers, and the fluctuations in all three ATPase activities were greater in the patients than in the volunteers. Even though the mean Ca2+-ATPase activity was higher during manias and euthymic periods than during depressions, mood and ATPase activities did not correlate with each other in all patients. Lithium carbonate treatment did not alter the ATPase activities, and the quantity of vanadium present in the membranes could not account for the variations in the enzyme activities observed. We suggest that either the RBCs of manic-depressive patients are very sensitive to fluctuations of a lipophilic ATPase activity--regulating factor present in plasma or the patients have at times high levels of such a factor. In some patients, the level of this hypothesized regulator may fluctuate in synchrony with mood changes.

Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = -.66, P less than .05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.

Seasonal affective disorder (SAD) is a syndrome characterized by recurrent depressions that occur annually at the same time each year. We describe 29 patients with SAD; most of them had a bipolar affective disorder, especially bipolar II, and their depressions were generally characterized by hypersomnia, overeating, and carbohydrate craving and seemed to respond to changes in climate and latitude. Sleep recordings in nine depressed patients confirmed the presence of hypersomnia and showed increased sleep latency and reduced slow-wave (delta) sleep. Preliminary studies in 11 patients suggest that extending the photoperiod with bright artificial light has an antidepressant effect.

Cerebrospinal fluid (CSF) monoamine metabolite levels were studied in 20 arsonists, 20 habitually violent offenders, and ten healthy inpatient volunteers. The arsonists and violent offenders had been in prison an average of six months before the study. Both the raw data and data adjusted by analysis of covariance for group differences in age, height, sex, and season of the lumbar puncture showed significantly lower concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in the arsonists than in the other groups. The finding remained the same when arsonists with violent suicide attempts were excluded from the analysis. Although CSF concentrations of MHPG or 5-HIAA did not correlate with the severity of repeated fire-setting behavior, low blood glucose nadir in the oral glucose tolerance test (a measure of the tendency toward hypoglycemia) did. These results support the hypothesis that poor impulse control in criminal offenders is associated with low levels of certain CSF monoamine metabolites and with a hypoglycemic tendency.

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 urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in unipolar depressed patients before and during the fourth week of treatment with either imipramine hydrocloride or amitriptyline hydroxhloride. On the basis of strict rating criteria, 24 patients were selected as either unequivocal responders or nonresponders. In the imipramine group the mean pretreatment MHPG was significantly lower in the nine responders in the seven nonresponders; the converse was found with the amitriptyline patients. Of particular interest is that there was no overlap in individual values between the responders and nonresponders to either drug. Treatment with eigher imipramine or amitriptyline was associated with a significant decrease in MHPG excretion, which was independent of clinical response.

Maintenance tricyclic antidepressants induced rapid cycling between mania and depression in five female bipolar (manic-depressive) patients. Lithium carbonate did not prevent the tricyclic-induced rapid cycling, although two patients subsequently responded well to lithium carbonate alone. In these patients, the action of tricyclics can be conceptualized as accelerating rather than counteracting the natural, cyclic course of the illness in all of its phases. In this respect, tricyclics are analogous to several other drugs that are capable of modulating the frequency of oscillatory biological processes.

The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake sites for serotonin. Since there is an excellent correlation between the relative potencies of a series of antidepressants in displacing 3H-imipramine from binding sites in human brain and platelet, we have examined the binding of 3H-imipramine to platelets from 14 depressed patients and 28 age- and sex-matched controls. A highly significant decrease in the number of 3H-imipramine binding sites, with no significant change in the apparent affinity constants, was observed in platelets from the depressed patients compared with the controls. These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression.

Animal studies and some of thephenomena associated with alcoholism in humans suggest that some central effects of alcohol may involve serotonergic systems. The CSF metabolites of serotonin and dopamine, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were studied in hospitalized alcoholics. There were no significant differences in HVA levels between groups. The level of 5HIAA of alcoholics in the abstinence phase, 28 to 63 days after their last drink, was significantly lower (21.8 +/- 1.9 ng/mL) than both a nonalcoholic comparison group (31.7 +/- 2.0 ng/mL) and alcoholics in the immediate postintoxication phase, within one to two days after their last drink (32.3 +/- 2.9 ng/mL).

The metabolites of serotonin, dopamine, and norepinephrine, 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), respectively, were studied in cerebrospinal fluid of patients with acute schizophrenia. Base line levels of these metabolites were not significantly different from those in normal, neurological, and affectively ill controls. Accumulations of 5HIAA and HVA following probenecid administration, which provide a measure of serotonin and dopamine turnover, were also not significantly different in patients with acute schizophrenia and affective illness. After patients had recovered from their acute schizophrenic illness, HVA accumulations were significantly reduced. We discuss results in relation to amine hypotheses of schizophrenia and the suggestion that altered dopamine metabolism may reflect a biological change predisposing to acute schizophrenia.

We describe a rapid and sensitive radioreceptor assay for measuring benzodiazepines in plasma. This method is based on the competition between tritiated diazepam and pharmacologically active benzodiazepines present in plasma, for binding sites on rat brain synaptosomal membranes. No interference is obtained with drug-free plasma or plasma samples containing high concentrations of other commonly used drugs. High correlations (r = 0.98; P less than .001) were obtained between the "diazepam equivalents" measured in plasma with the radioreceptor assay and the levels of diazepam and nordiazepam obtained by gas-liquid chromatography. The radioreceptor assay is rapid, sensitive, specific, and requires no sophisticated equipment or methods. It should therefore prove useful in monitoring blood benzodiazepine levels for both therapeutic and toxicologic purposes.

Single-dose prediction of ultimate steady-state concentrations of tricyclic antidepressants at the outset of treatment can be a valuable therapeutic tool that has had only limited application. We demonstrate accurate steady-state predictions following both the tertiary amine, imipramine hydrochloride, and the secondary amine, desipramine hydrochloride, in a carefully monitored long-term treatment patient population. Results show that long-term treatment does not alter metabolism of either imipramine or desipramine. The relative merits of single-dose predictions using total and "abbreviated" areas under the curve and concentration at 24 hours are compared. These findings demonstrate that single-dose prediction can be used as a practical therapeutic, as well as, research tool.

Nineteen patients, each hospitalized with a major depressive episode, were deprived of sleep for one night. Ten patients responded with clear improvement in depressive symptoms; the substantial clinical change was transient, usually lasting one day. Those who responded had significantly higher initial depression ratings (P less than .01) and tended to be older than nonresponders who experienced mild increases in irritability, fatigue, and discomfort following sleep deprivation. Amine metabolites, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were not substantially affected by sleep deprivation, although there was a significant interaction of clinical response and direction of 3-methoxy-4-hydroxyphenylglycol (MHPG) change. Sleep deprivation thus produces acute, but only transient improvement in a selected group of severely depressed patients; it appears to be an important tool in the study of the affective disorders.