The role of serotonin and dopamine in the pathophysiology of obsessive compulsive disorder.
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Brain↗
Biomedical subjects
L H Price
Publications and source records attributed to L H Price.
Acute exacerbation of body dysmorphic disorder during tryptophan depletion.
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Acute Disease↗
Serotonin syndrome.
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Depressive Disorder↗
Serotonergic dysfunction in depression associated with Parkinson's disease.
A 55-year-old man presented with a 5-year history of Parkinson's disease and a 6-month history of major depression. The patient's depressive symptoms responded to treatment with fluvoxamine, a selective and potent serotonin reuptake inhibitor. Tryptophan depletion testing, which acutely lowers central serotonin levels, caused a brief exacerbation of the depressive illness, which resolved upon tryptophan repletion. Serotonergic dysfunction may be an etiologic factor in depression that occurs in Parkinson's disease.
Depressive Disorder↗
Chronic 3,4-methylenedioxymethamphetamine (MDMA) use: effects on mood and neuropsychological function?
3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in animals. There is now preliminary evidence in humans of 5-HT deficits associated with extensive use of MDMA. In order to begin to describe the cognitive and mood effects of chronic MDMA use, nine individuals with extensive MDMA use histories were studied. Despite the absence of memory deficits on clinical examination, a pattern of mild-to-moderate impairment was observed on both the Initial and Delayed Paragraph Tests of the Wechsler Memory Scale; eight of the subjects had at least mild impairment on at least one test in the neuropsychological battery. Despite previously reported suggestive evidence of 5-HT deficit in this group, none reported depressed mood or met clinical criteria for an affective disorder at the time of testing. These preliminary findings raise concern about possible detrimental effects of MDMA use on neuropsychological function for future systematic study and they highlight important issues regarding the effects of 5-HT deficits on cognitive function and mood regulation.
3,4-Methylenedioxyamphetamine↗
Assessment of severity and change in obsessive compulsive disorder.
Useful clinician-rated measures of OCD are now available. The Y-BOCS and NIMH Global OC both seem suitable for monitoring outcome in drug trials of OCD. These two scales seem relatively specific for symptoms of OCD and are sensitive to drug-induced changes in symptoms. Neither the Y-BOCS nor the NIMH Global OC confuse trait with state. There are ample data suggesting that the Y-BOCS is reliable and valid scale. Unlike some of the symptom inventories, such as the LOI and MOCI, final scores on the NIMH Global OC and Y-BOCS are not influenced directly by the type or number of obsessions and compulsions present. A computer-administered version of the Y-BOCS has been developed. Currently available patient-rated instruments suffer from serious shortcomings, including insensitivity to change and poor representation of patients with mono-symptomatic clinical pictures (e.g., hoarding alone). Some rating scales have been adapted for use in children with OCD. Several groups, including our own, have elected to use change scores on the 10-item Y-BOCS and a global measure of OCD, such as the NIMH Global OC or modified OGI, as the principal outcome variables in drug trials in patients with OCD. Several studies have selected a 35% decrease in Y-BOCS scores from baseline as indicative of clinically significant improvement. A limitation of all single-item global measures is that they cannot be resolved into smaller components. The more fine-grained analysis that is possible with the multi-item Y-BOCS makes it more desirable as a primary outcome measure, with a global scale as a secondary outcome measure.
Adult↗
The serotonin hypothesis of obsessive compulsive disorder: implications of pharmacologic challenge studies.
Demonstration of the efficacy of serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors such as clomipramine in the treatment of obsessive compulsive disorder has fueled interest in the neurobiological basis of this illness. Results of treatment studies, investigations of biological markers, and pharmacologic challenges are reviewed and implications for a 5-HT theory of obsessive compulsive disorder discussed. While the nature of the dysregulation in serotonin transmission that may attend obsessive compulsive disorder has yet to be fully elucidated, evidence accumulates that 5-HT function in part modulates obsessive compulsive symptoms. Development of more specific probes and new brain imaging techniques will further enhance understanding of the pathophysiology of obsessive compulsive disorder.
Biomarkers↗
Pharmacotherapy of obsessive compulsive disorder.
The authors briefly review studies of the efficacy of potent serotonin reuptake inhibitors (SRIs) (e.g., clomipramine, fluvoxamine) in obsessive compulsive disorder (OCD) and compare the use of antidepressants in the treatment of depression and OCD. They propose an algorithm for those patients with OCD who fail to respond to an adequate trial with a potent SRI and discuss the promise and limitations of adding tryptophan, fenfluramine, lithium, buspirone, or a neuroleptic to ongoing SRI therapy. Other biological approaches (e.g., ECT, psychosurgery) are considered in terms of their narrowly defined roles in the treatment of patients with SRI-resistant OCD.
1-Naphthylamine↗
Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects.
Ten healthy male subjects were administered i.v. meta-chlorophenylpiperazine (MCPP) (0.1 mg/kg) after oral ritanserin (5-10 mg), a putative 5HT1c/5HT2 (serotonin) antagonist, or placebo. Behavioral responses, cardiovascular effects, and neuroendocrine responses (cortisol, growth hormone, and prolactin) were measured serially for 4 hours after MCPP infusion. Premedication with ritanserin attenuated the MCPP-induced increases in self-rated anxiety and prolactin, and completely antagonized MCPP cortisol elevations. In contrast, ritanserin did not significantly alter growth hormone response to MCPP. These findings suggest a role for 5-HT1c/5-HT2 receptors in the endocrine and behavioral responses to the mixed serotonin agonist MCPP in humans.
Adult↗
SPECT regional cerebral blood flow and neuropsychological testing in non-demented HIV-positive drug abusers: preliminary results.
1. Non-demented HIV seropositive and seronegative methadone maintained patients and healthy volunteers (n = 10 each) participated. 2. All subjects underwent SPECT regional cerebral blood flow scanning following injection of Tc-99m HMPAO. All patients underwent neuropsychologic (NP) testing. 3. The left striatum/whole brain blood flow ratio was elevated in the HIV positive group compared to the healthy subjects. Two HIV positive patients had clearly abnormal striatal ratios. Both groups were impaired on NP testing; HIV+ patients were somewhat more impaired on tests of sustained attention and verbal memory. 4. SPECT scanning with Tc-99 HMPAO may identify a subgroup of HIV positive patients with evidence of CNS involvement prior to onset of dementia symptoms.
AIDS Dementia Complex↗
Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy comparison subjects.
OBJECTIVE: This study was designed to compare central serotonergic function in depressed patients and healthy comparison subjects by examining neuroendocrine and mood responses to intravenous L-tryptophan. METHOD: One hundred twenty-six drug-free patients with DSM-III-R major depression (109 unipolar, 17 bipolar; 68 melancholic, 58 nonmelancholic; 28 psychotic, and 98 nonpsychotic patients) and 58 healthy comparison subjects participated. After an overnight fast, subjects received an intravenous infusion of L-tryptophan, 7 g. Blood was obtained for determination of serum prolactin, serum growth hormone (GH), and plasma tryptophan levels. Visual analogue scales were used to assess mood. RESULTS: Prolactin responses were blunted in nonmelancholic and higher in melancholic and psychotic depressed patients, while GH responses were blunted in combined unipolar, nonmelancholic, and nonpsychotic depressed patients. Controlling for baseline biological, clinical, and demographic factors eliminated the higher prolactin response in the melancholic and psychotic patients, attenuated the blunted GH response in the unipolar patients, and revealed a blunted GH response in the melancholic patients. Patients and comparison subjects differed on five of 13 mood responses, primarily because of baseline differences. CONCLUSIONS: These findings are consistent with previous studies demonstrating blunted neuroendocrine responses to intravenous L-tryptophan in depression. Restriction of these findings to specific subtypes of depression may reflect a differential role of serotonergic abnormalities in these subtypes.
Adult↗
Clinical phenomenology and neurobiology of cocaine abstinence: a prospective inpatient study.
OBJECTIVE: This study was undertaken to document symptoms and changes in dopaminergic function emerging after abrupt cessation of cocaine use. METHOD: After admission, 22 patients with DSM-III-R cocaine dependence were observed drug free for 3 weeks. The patient-rated Ribicoff Abstinence Rating Scale, Symptom Rating Scale, Physical Symptom Scale, Patient Rated Anxiety Scale, Beck Depression Inventory, and visual analogue scales for 16 subjective states were completed daily, and nurses rated 13 patients with the global anxiety and depression items of the Short Clinical Rating Scale. Serial blood samples were obtained three times weekly, and the patients' levels of prolactin, growth hormone (GH), and homovanillic acid (HVA) were measured. Their prolactin and GH values were compared with those of matched normal subjects. RESULTS: A total of 62 subjective symptom variables were evaluated. At baseline, the symptom ratings were mildly elevated. At 3 weeks there were significant decreases from baseline in 28 variables and nearly significant decreases in six additional variables. Nurse-rated anxiety and depression also changed, but in a more variable pattern. There was a small but significant increase from baseline over time in plasma prolactin, but there were no significant changes in GH or HVA. The patients' prolactin and GH values did not differ from those of the normal subjects. CONCLUSIONS: These findings suggest that symptoms after inpatient cessation of uncomplicated cocaine addiction are relatively mild and decrease linearly over the first month. Evidence of dysregulated central dopamine function was limited. The findings do not support routine use of pharmacological agents in the inpatient management of such patients.
Adult↗
Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression.
Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported on the effects of rapid dietary TRP depletion in psychiatric patients; this study extends those reports and summarizes the effects of rapid TRP depletion on mood in depressed patients. One hundred and fifteen depressed (according to DSM-III-R) patients (69 drug free and symptomatic; 46 in clinical remission after antidepressant treatment) received tryptophan depletion testing in a double-blind, placebo-controlled, crossover fashion. Of 69 symptomatic, drug-free, depressed patients, 30 percent were unchanged the day of the tryptophan-free drink (TFD), but became clinically less depressed the day after the TFD. Although 80 percent of monoamine oxidase inhibitor- or fluvoxamine-treated patients experienced a depressive relapse during TRP depletion testing, only 18 percent of desipramine-treated patients relapsed. Brain 5-HT function may be intimately involved in the modulation of some affective states and in the mechanism of action of some antidepressant medications.
Antidepressive Agents↗
A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive-compulsive disorder: lack of efficacy.
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.
Adult↗
Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan.
Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.
Adult↗
Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder. Comparison of fluvoxamine and desipramine.
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).
Adult↗
Fluvoxamine treatment of coincident autistic disorder and obsessive-compulsive disorder: a case report.
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.
Adult↗
Lithium and serotonin function: implications for the serotonin hypothesis of depression.
Lithium enjoys wide clinical use in the treatment of affective disorders, but the mechanism of its action in these conditions is still controversial. Recent studies have shown that lithium can interact with other antidepressant drugs to enhance their efficacy, perhaps by specific effects on serotonin (5-HT) function. A large body of independent evidence suggests that 5-HT function is abnormal in depression. This review documents preclinical evidence of lithium's effects on 5-HT function at the levels of precursor uptake, synthesis, storage, catabolism, release, receptors, and receptor-effector interactions. The weight of this evidence suggests that lithium's primary actions on 5-HT may be presynaptic, with many secondary postsynaptic effects. Studies in humans, using very different methodological approaches, generally suggest that lithium has a net enhancing effect on 5-HT function. These actions of lithium may serve to correct as-yet unspecified abnormalities of 5-HT function involved in the pathogenesis of depression.
Animals↗