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Two- and 4-week double-blind placebo-controlled trials of lithium augmentation of ongoing fluvoxamine treatment trials were conducted in 20 and 10 patients, respectively, with primary obsessive-compulsive disorder (OCD) who had failed to respond to fluvoxamine alone. Although 2 weeks of double-blind lithium augmentation produced a small but statistically significant reduction in obsessive-compulsive symptoms, most patients did not have a clinically meaningful response. Furthermore, there was no statistical or clinical improvement in obsessive-compulsive symptoms during the subsequent 4-week double-blind, placebo-controlled trial of lithium augmentation. On the basis of treatment response criteria, only 18% and 0% of the patients responded to lithium augmentation of fluvoxamine during the 2- and 4-week treatment trials, respectively. In light of the previously reported 44% response rate to lithium augmentation in treatment-resistant depressed patients on fluvoxamine, the results of this study suggest that pathophysiological differences may exist between OCD and depression. The routine use of lithium augmentation in the management of patients with OCD who are refractory to serotonin reuptake inhibitors is not supported by these findings.

Patients with obsessive-compulsive disorder (OCD) had lower right-ear advantages than healthy controls on five different language-related dichotic listening tests of cerebral laterality. This abnormality was more pronounced in patients with more severe illness. Stimulus pairs in one test consisted of one word with a positive emotional valence and one emotionally neutral word. Pairs in another test consisted of one negative and one neutral word. Patients with OCD tended to hear fewer emotion-related words than did healthy controls, a finding also noted in depressed patients. Moreover, OCD patients who responded to treatment with serotonin reuptake inhibitors heard fewer emotion-related words than did nonresponders.

This is a single-case report of fluvoxamine treatment of comorbid autistic disorder (AD) and obsessive-compulsive disorder (OCD). Psychological, neuroanatomical, and neurochemical parallels are drawn between AD and OCD. The implications of this case of coincident AD and OCD, as well as the response to fluvoxamine, are discussed with respect to nosology, pathophysiology, and treatment of these disorders.

A 25-year-old man with a history of Tourette's syndrome presented for treatment of OCD symptoms. Fluvoxamine worsened tics, led to coprolalia, and did not help the OCD. The addition of pimozide dramatically reduced both OCD and Tourette's symptoms. Double-blind sequential discontinuation of fluvoxamine and pimozide confirmed that pimozide alone reduced only tics and the combination of fluvoxamine and pimozide was required for the improvement in OCD. Tics may reflect a subtype of OCD. Some OCD patients unresponsive to a 5-HT reuptake inhibitor alone may benefit from the addition of a dopamine antagonist.

It seems unlikely that a solitary disturbance in serotonin function can fully account for the pathophysiology of obsessive compulsive disorder. The authors propose that some forms of obsessive compulsive disorder, e.g., obsessive compulsive disorder with a history of Tourette's syndrome, may involve a relative or absolute derangement in both brain serotoninergic and dopaminergic systems. A role for dopamine in the pathophysiology of obsessive compulsive disorder is supported by a review of the preclinical and clinical evidence. Additional studies are needed to more directly evaluate dopamine function in patients with obsessive compulsive disorder.

To evaluate whether serotonin reuptake inhibition is critical to the treatment of obsessive-compulsive disorder, 40 outpatients with a principal diagnosis of obsessive-compulsive disorder were randomized in a double-blind fashion to 8 weeks of treatment with either the serotonin reuptake inhibitor fluvoxamine maleate (n = 21) or the norepinephrine reuptake inhibitor desipramine hydrochloride (n = 19). Fluvoxamine was significantly better than desipramine in reducing the severity of obsessive-compulsive symptoms, as measured by the Yale-Brown Obsessive Compulsive Scale and by the global response rate ("responder" equaling "much improved"). Eleven of 21 patients were responders with fluvoxamine compared with 2 of 19 patients with desipramine. Fluvoxamine, but not desipramine, was also effective in reducing the severity of "secondary" depression. Fluvoxamine-induced improvement in symptoms of obsessive-compulsive disorder was not correlated with the severity of baseline depressive symptoms. This study provides additional evidence that the acute serotonin reuptake properties of a drug are predictive of its anti-obsessive-compulsive efficacy. It is hypothesized that the mechanism of action of serotonin reuptake inhibitors in obsessive-compulsive disorder may be related to chronic treatment-induced adaptive changes in presynaptic serotonin receptor function (eg, autoreceptor desensitization) and/or indirect influences on dopaminergic function (eg, in the basal ganglia).

Nine of 17 patients with obsessive-compulsive disorder responded when neuroleptic was added to fluvoxamine with or without lithium. Comorbid occurrence of tic spectrum disorders or of schizotypal personality disorder was associated with response. Abnormalities in brain dopamine and serotonin may be implicated in such patients.

In view of evidence that brain serotonin (5-HT) function is abnormal in depression, the ability to alter 5-HT function has been studied as a mechanism of antidepressant drug action. In preclinical studies, antidepressants had significant effects on 5-HT receptor sensitivity. In the clinical setting, the pharmacologic challenge paradigm has generated interest as a means of studying 5-HT function. Most frequently used in these studies has been intravenous L-tryptophan (L-TRP), which increases serum prolactin (PRL). The authors review the neuroendocrine effects of intravenous L-TRP in depression and other conditions, as well as the effects of thymoleptic drugs on the PRL response to L-TRP. Findings are discussed in light of recent evidence that experimentally reduced plasma TRP can reverse the therapeutic effects of some antidepressants.

1. Preclinical studies reveal that long-term treatment with antidepressant drugs induces significant changes in serotonergic (5-HT) receptor sensitivity. Similarly, clinical studies suggest that brain 5-HT function is abnormal in depression. Of the available methodologies for conducting such clinical studies, the pharmacological challenge strategy has proven particularly useful. 2. I.v. L-TRP has emerged as the most frequently used challenge agent in diagnostic and neuropsychopharmacological studies of 5-HT function. I.v. L-TRP increases serum prolactin (PRL) in humans, probably via 5-HT mechanisms. Under carefully standardized conditions, this PRL response to L-TRP appears to be a reasonably sensitive and valid measure of net 5-HT function. 3. The PRL response to L-TRP is blunted in depressed patients compared with healthy controls. Blunting has not been observed in panic disorder, obsessive compulsive disorder, or schizophrenia, although preliminary findings suggest it may occur in bulimia. 4. The PRL response to L-TRP is enhanced by certain classes of thymoleptic drugs (TCAs, MAOIs, 5-HT reuptake inhibitors, lithium) in a differentially time-dependent fashion. So-called "atypical" antidepressants (trazodone, mianserin) and benzodiazepines have no effect. Such findings are generally consistent with preclinical electrophysiological findings. 5. These clinical studies of the PRL response to L-TRP, in conjunction with emerging evidence that experimentally reduced plasma TRP can reverse the therapeutic effects of some antidepressants, suggest that antidepressant drug action may be more accurately conceptualized as 5-HT dependent rather than 5-HT enhancing. The availability of more selective 5-HT-active drugs promises to further clarify 5-HT mechanisms of neuropsychiatric disease and drug action at the clinical level.

The effectiveness of clonidine hydrochloride in the treatment of abrupt withdrawal from long-term, therapeutic doses of benzodiazepines was studied in three patients under double-blind, placebo-controlled conditions. The intensity, severity, and duration of the abstinence syndrome were not altered by clonidine at a dose sufficient to markedly reduce blood pressure and plasma free 3-methoxy-4-hydroxyphenylglycol. These results contrast with the established efficacy of clonidine in the opiate withdrawal syndrome and suggest that many of the symptoms of benzodiazepine withdrawal may not be caused by hyperactivity of the noradrenergic system.

Ten obsessive-compulsive patients received single-blind treatment with fluvoxamine, a selective serotonin reuptake inhibitor, for several weeks following at least 2 weeks of placebo. The group showed significant improvement, as measured by several clinical scales and self-ratings; six patients were judged responders. Fluvoxamine appears effective in treating severe obsessive-compulsive disorder.

The effects of yohimbine, an alpha 2-adrenergic receptor antagonist, on anxiety, blood pressure, heart rate, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and cortisol were determined in 20 healthy subjects and 68 patients who had agoraphobia with panic attacks or panic disorder. Yohimbine produced panic attacks meeting DSM-III criteria in 37 patients and one healthy subject. The patients reporting yohimbine-induced panic attacks had significantly larger increases in plasma MHPG, cortisol, systolic blood pressure, and heart rate than the healthy subjects. These findings support the hypothesis relating high noradrenergic neuronal activity to the pathophysiology of panic attacks in a subgroup of panic disorder patients.

One hypothesis that could account for the anxiogenic response to breathing air supplemented with carbon dioxide seen in panic anxiety patients is that panic patients might have abnormally high central medullary chemoreceptor sensitivity. Chemoreceptor sensitivity was assessed by using a rebreathing technique to measure the ventilatory response to CO2 in 14 medication-free patients with agoraphobia and panic attacks and 23 healthy subjects. Ventilatory response to CO2 was similar in patients and controls (mean +/- SEM, 1.58 +/- 0.16 vs 1.58 +/- 0.14 L/min/mm Hg), suggesting that abnormal chemoreceptor sensitivity does not explain the behavioral sensitivity of panic patients to CO2. Anxiety ratings increased markedly during rebreathing both in patients and controls; anxiety increases were significantly greater in patients than in healthy subjects matched for age, sex, and rebreathing duration. Alprazolam treatment in eight patients markedly attenuated anxiety increases during rebreathing. Differences in anxiogenic sensitivity to CO2 between patients and controls may be due to differences in the regulation of noradrenergic or other neuronal systems.

The studies reviewed here suggest that the potent and selective serotonin reuptake inhibitor fluvoxamine is an effective treatment for OCD. Response to the antiobsessional effects of fluvoxamine is independent of baseline levels of depression. Additional studies are currently underway to determine if fluvoxamine is actually more effective in OCD than less potent blockers of serotonin reuptake (e.g., desipramine) (Goodman et al. unpublished data). However, since the clinical response to potent serotonin reuptake blockers is often incomplete or, in as many as one-third of patients, absent, the precise relevance of the monoamine reuptake blocking properties of these medications to the pathogenesis of OCD remains unclear.

The Yale-Brown Obsessive Compulsive Scale was designed to remedy the problems of existing rating scales by providing a specific measure of the severity of symptoms of obsessive-compulsive disorder that is not influenced by the type of obsessions or compulsions present. The scale is a clinician-rated, 10-item scale, each item rated from 0 (no symptoms) to 4 (extreme symptoms) (total range, 0 to 40), with separate subtotals for severity of obsessions and compulsions. In a study involving four raters and 40 patients with obsessive-compulsive disorder at various stages of treatment, interrater reliability for the total Yale-Brown Scale score and each of the 10 individual items was excellent, with a high degree of internal consistency among all item scores demonstrated with Cronbach's alpha coefficient. Based on pretreatment assessment of 42 patients with obsessive-compulsive disorder, each item was frequently endorsed and measured across a range of severity. These findings suggest that the Yale-Brown Scale is a reliable instrument for measuring the severity of illness in patients with obsessive-compulsive disorder with a range of severity and types of obsessive-compulsive symptoms.

A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. We report on the presence of elevated concentrations of dynorphin A [1-8] in the CSF of 7 TS patients, aged 20 to 45 years. The increase in CSF dynorphin was found to be associated with the severity of the obsessive compulsive symptoms but not with tic severity in these patients. Although CSF studies lack the precision necessary to address questions of selective involvement of neuronal system in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiology of TS and related disorders. Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) (1). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case per 10,000 girls, and milder variants of the syndrome are likely to occur in a sizeable percentage of the population (2). Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consistent with an autosomal dominant form of inheritance (3,4). Neurobiologic and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and basal ganglia structures remain the prime candidates as the neuroanatomical origin for TS and related conditions (1). Endogenous opioids, including dynorphin and met-enkephalin are concentrated in structures of the basal ganglia (5), are known to interact with central dopaminergic neurons (6, 7), and may play an important role in the control of motor functions (8). Post-mortem brain studies have directly implicated opioids in the pathophysiology of Parkinson's disease (9), Huntington's disease (10), and most recently in TS (11). The neuropathological study of Haber et al. (11) reported decreased levels of dynorphin A [1-17] immunoreactivity in striatal fibers projecting to the globus pallidus in the brain of a patient with severe TS. This ovservation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS.(ABSTRACT TRUNCATED AT 400 WORDS)

Tricyclic antidepressants, monoamine oxidase inhibitors, and antidepressants of atypical structure are used in a variety of psychiatric and nonpsychiatric disorders. The efficacy of antidepressant drugs in major depression, panic disorder, obsessive-compulsive disorder, peptic ulcer disease, enuresis, chronic pain, migraine, bulimia, and attention deficit disorder is briefly reviewed. The rationale that led to each of these therapeutic applications is examined, and the possible mechanism of action is discussed in light of recent advances in neurobiologic research. It is concluded that improved understanding of antidepressant drugs' mechanisms of action may help elucidate the etiology of these disorders and yield more effective treatments.

To evaluate the role of serotonin (5-HT) function in obsessive-compulsive disorder (OCD), behavioral and biochemical responses to the 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) and the 5-HT precursor tryptophan were examined in healthy subjects and patients with OCD. Baseline prolactin levels and the prolactin rise following MCPP were significantly reduced in female patients compared with female healthy subjects. In contrast, the increase in prolactin level following tryptophan administration was not significantly different between male or female patients with OCD and the respective sex-matched healthy subjects. The prolactin responses to MCPP and tryptophan were both significantly higher in female patients and healthy subjects than in their male counterparts. The cortisol and growth hormone responses to MCPP and tryptophan were similar in the patients and healthy subjects and were not related to gender. The behavioral responses to MCPP or tryptophan were not consistently different between patients and healthy subjects, and neither MCPP nor tryptophan had effects on obsessive or compulsive symptoms. These results lend only partial support to the hypothesis that 5-HT dysfunction may be linked to the pathophysiology of OCD and point to the need for the evaluation of other neurotransmitter systems in future investigations of OCD.

To assess the role of serotonin function in the development of panic anxiety, the behavioral and biochemical responses to the serotonin receptor agonist, m-chlorophenylpiperazine (MCPP) was examined in healthy subjects and agoraphobic and panic disorder patients. MCPP had anxiogenic effects in both the healthy subjects and patients. Panic attacks meeting DSM-III criteria occurred following MCPP in 12 of 23 patients and 6 of 19 healthy subjects (NS) and other ratings of anxiety also did not distinguish the two groups. MCPP resulted in significant but similar increases in cortisol, prolactin, and growth hormone in the healthy subjects and patients. The results of this investigation suggest that serotonin neuronal dysfunction may not be of etiologic significance in most panic disorder patients. However, the observed anxiogenic properties of MCPP suggest that additional studies of the role of serotonin systems in the pathophysiology of human anxiety disorders are indicated.

Data from 74 patients with panic disorder were evaluated to determine the comparative efficacy of imipramine, alprazolam, and trazodone. All patients were treated with placebo for 3 weeks and were then blindly switched to active treatment for 8 weeks. Both imipramine and alprazolam were highly effective in reducing the symptoms of generalized anxiety, the frequency of panic attacks, and phobic avoidance. However, the time course of these effects differed; alprazolam demonstrated therapeutic properties during the first week, whereas the therapeutic efficacy of imipramine was not clearly apparent until the fourth week of treatment. Relative to imipramine and alprazolam, trazodone was not an effective treatment for panic disorder and was poorly tolerated; only 17 trazodone-treated patients completed at least 4 weeks of treatment, and only 2 patients were considered good or complete responders. These findings support the hypotheses that drugs that are efficacious in the treatment of panic disorders act by altering noradrenergic function and that drugs with primary actions on serotonin function are likely to be less effective treatments. The different time courses of therapeutic action of imipramine and alprazolam indicate that these drugs ameliorate panic anxiety via different mechanisms. The possible therapeutic applications of this observation are discussed.

Carbon dioxide was administered for 15 minutes to patients with panic disorders (5% CO2, n = 14) and healthy subjects (5% CO2, n = 11; 7.5% CO2, n = 8). Following administration of CO2 and air placebo, changes in behavioral ratings, vital signs, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, cortisol, growth hormone, and prolactin were measured over three hours. In the healthy subjects, CO2 produced dose-related increases in anxiety, somatic symptoms, vital signs, and plasma cortisol levels. In the patients, the frequency of panic attacks (in eight of 14 patients) and the increases in anxiety and somatic symptoms induced by 5% CO2 exceeded those in the healthy subjects and were similar to those induced by 7.5% CO2 in the healthy subjects. The physiologic and biochemical measurements obtained did not elucidate the mechanisms underlying CO2-induced anxiety or the greater anxiogenic effects of CO2 seen in patients with panic disorders.

The alpha 2-adrenergic receptor antagonist yohimbine was administered to 12 drug-free patients with obsessive compulsive disorder (OCD) and to 12 healthy subjects. Changes in behavior, cardiovascular symptoms, and in plasma levels of cortisol and the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed. Yohimbine had no significant effect on OCD symptoms. The OCD patients did not differ from healthy controls in their behavioral and MHPG response to yohimbine. In contrast to healthy subjects, OCD patients, like previous reports of depressed and panic disorders patients, had an increased cortisol response to yohimbine. These data suggest it is unlikely that abnormal noradrenergic function plays a primary role in the pathogenesis of OCD.

A six- to eight-week double-blind placebo-controlled trial of the potent and selective serotonin reuptake inhibitor fluvoxamine was conducted in 42 patients with primary obsessive-compulsive disorder (OCD). Approximately one half of the patients also had symptoms of major depression. Fluvoxamine was significantly better than placebo on all measures of obsessive-compulsive symptoms. Nine of 21 patients were responders ("much improved") with fluvoxamine compared with no responders with placebo, and fluvoxamine was effective in patients with OCD both with and without secondary depression. Response of OCD was not correlated with severity of baseline depression. These data lend partial support to the serotonin hypothesis of OCD. However, since a number of patients failed to respond to fluvoxamine, the role of other neurochemical systems in this disorder needs to be explored.

A patient developed manic symptoms during treatment with alprazolam. These symptoms remitted upon discontinuation of treatment, but reemerged during a second trial with alprazolam. Subsequent administration of an equivalent dosage of lorazepam did not induce manic symptoms. The clinical and theoretical implications of these findings are discussed in relation to the possible mechanisms of action of alprazolam, a novel benzodiazepine.

The development design and reliability of the Yale-Brown Obsessive Compulsive Scale have been described elsewhere. We focused on the validity of the Yale-Brown Scale and its sensitivity to change. Convergent and discriminant validity were examined in baseline ratings from three cohorts of patients with obsessive-compulsive disorder (N = 81). The total Yale-Brown Scale score was significantly correlated with two of three independent measures of obsessive-compulsive disorder and weakly correlated with measures of depression and of anxiety in patients with obsessive-compulsive disorder with minimal secondary depressive symptoms. Results from a previously reported placebo-controlled trial of fluvoxamine in 42 patients with obsessive-compulsive disorder showed that the Yale-Brown Scale was sensitive to drug-induced changes and that reductions in Yale-Brown Scale scores specifically reflected improvement in obsessive-compulsive disorder symptoms. Together, these studies indicate that the 10-item Yale-Brown Scale is a reliable and valid instrument for assessing obsessive-compulsive disorder symptom severity and that it is suitable as an outcome measure in drug trials of obsessive-compulsive disorder.