Deep brain stimulation in early Parkinson's disease: enrollment experience from a pilot trial.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an accepted therapy for advanced Parkinson's disease (PD). In animal models, pharmacologic ablation and stimulation of the subthalamic nucleus have resulted in clinical improvement and, in some cases, improved survival of dopaminergic neurons. DBS has not been studied in the early stages of PD, but early application should be explored to evaluate safety, efficacy, and the potential to alter disease progression. METHODS: We are conducting a prospective, randomized, single-blind clinical trial of optimal drug therapy (ODT) compared to medication plus DBS (ODT + DBS) in subjects with Hoehn & Yahr Stage II idiopathic PD who are without motor fluctuations or dementia. We report here subject screening, enrollment, baseline characteristics, and adverse events. RESULTS: 30 subjects (average age 60 ± 6.9 years, average duration of medicine 2.1 ± 1.3 years, average UPDRS-III scores 14.9 on medication and 27.0 off medication) are enrolled in the ongoing study. Twelve of 15 subjects randomized to DBS experienced perioperative adverse events, the majority of which were related to the procedure or device and resolved without sequelae. Frequently reported adverse events included wound healing problems, headache, edema, and confusion. CONCLUSION: This report demonstrates that subjects with early stage PD can be successfully recruited, consented and retained in a long-term clinical trial of DBS. Our ongoing pilot investigation will provide important preliminary safety and tolerability data concerning the application of DBS in early stage PD.

Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action.

BACKGROUND: Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported that rapid TRP depletion more frequently reversed the antidepressant response to monoamine oxidase inhibitors and 5-HT reuptake inhibitors than to desipramine (DMI). This study further investigates the relationship of relapse during TRP depletion to antidepressant type in nonrefractory, depressed patients randomly assigned to treatment with either DMI or fluoxetine (FLU). METHODS: Fifty-five drug-free depressed (DSM-III-R) patients were randomly assigned to antidepressant treatment with either DMI or FLU. All patients were either treatment naive (n = 34) or had previously received successful antidepressant treatment (n = 21). During the treatment phase, 35 patients had therapeutic responses by predetermined criteria (DMI 18/25; FLU 17/23) and 30 of these (15 DMI responders and 15 FLU responders) went on to TRP depletion testing. Patients received two 2-day test sessions involving administration of similar amino acid drinks. One session led to rapid TRP depletion and the other did not. Behavioral ratings [Hamilton Depression Scale (HDRS)] and plasma for TRP levels were obtained prior to, during, and after testing. Relapse was defined as a 50% increase in HDRS with total < or = 17. RESULTS: Total and free TRP decreased 70% to 80% 5 hours after the TRP-free drink. While 8/15 FLU responders relapsed, only 1/15 of the DMI responders relapsed. No patient experienced significant depressive symptoms during control testing. CONCLUSIONS: Rapid depletion of plasma TRP transiently reverses the antidepressant response in many patients on FLU but not DMI. Depressive relapse during TRP depletion appears to be more related to antidepressant type than to patient variables since patients were randomly assigned to the two treatments. Antidepressant response to FLU appears to be more dependent on 5-HT availability than that of DMI, suggesting that antidepressants mediate their therapeutic effects through different mechanisms.

Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse.

BACKGROUND: Short-term depletion of plasma tryptophan has been shown to result in depressive relapse in patients with remission of major depression. Positron emission tomography and single photon emission computed tomography studies implicated the dorsolateral prefrontal cortex, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression. The purpose of this study was to measure cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. METHODS: Patients diagnosed as having major depression (N = 21) who clinically improved with serotonin reuptake inhibitors underwent 2 test days involving tryptophan depletion or placebo, followed 6 hours later by positron emission tomography scanning with fludeoxy-glucose F18. Brain metabolism was compared in patients with (n = 7) and without (n = 14) a tryptophan depletion-induced depressive relapse. RESULTS: Tryptophan depletion resulted in a decrease in brain metabolism in the middle frontal gyrus (dorsolateral prefrontal cortex), thalamus, and orbitofrontal cortex in patients with a depletion-induced depressive relapse (but not in patients without depletion-induced relapse). Decreased brain metabolism in these regions correlated with increased depressive symptoms. Baseline metabolism was increased in prefrontal and limbic regions in relapse-prone patients. CONCLUSION: Specific brain regions, including the middle frontal gyrus, thalamus, and orbitofrontal cortex, may mediate the symptoms of patients with major depression.

Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder.

BACKGROUND: We have previously reported an increase in symptoms of anxiety in patients with posttraumatic stress disorder (PTSD) following administration of the beta 2-antagonist yohimbine, which stimulates brain norepinephrine release. Preclinical studies show decreased metabolism in the neocortex and the caudate nucleus with high-dose yohimbine-induced norepinephrine release, but low levels of norepinephrine release result in an increase in metabolism in these areas. METHODS: We used positron emission tomography and fludeoxyglucose F 18 to measure brain metabolism in Vietnam combat veterans with PTSD (n = 10) and healthy age-matched control subjects (n = 10), following administration of yohimbine (0.4 mg/kg) or placebo in a randomized, double-blind fashion. RESULTS: Yohimbine resulted in a significant increase in anxiety in the patients with PTSD, but not in healthy subjects. There was a significant difference in brain metabolic response to yohimbine in patients with PTSD compared with healthy subjects in prefrontal, temporal, parietal, and orbitofrontal cortexes. Metabolism tended to decrease in patients with PTSD and increase in healthy subjects following administration of yohimbine. CONCLUSION: These findings are consistent with our previous hypothesis of enhanced norepinephrine release in the brain with yohimbine in patients with PTSD.

Lack of behavioral effects of monoamine depletion in healthy subjects.

This study was designed to determine the behavioral effects of a reduction in catecholamine and indoleamine function in healthy subjects. Eight healthy subjects received the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) in combination with a full-strength tryptophan-depleting amino acid drink during one 4-day test session, and AMPT and tryptophan-supplemented amino acid drink (n = 2), or a 25% strength tryptophan-depleting amino acid drink (n = 6) during a second 4-day test session. The combined administration of AMPT and the tryptophan-free amino acid drink did not produce statistically significant or even clinically noticeable changes in mood among the healthy subjects. The implications of these observations for the monoamine hypotheses of depression are discussed.

Effects of alpha-methyl-para-tyrosine (AMPT) in drug-free depressed patients.

A variety of biologic studies have demonstrated abnormal regulation of the norepinephrine (NE) system in patients with major depression, suggesting a role for NE in the etiology of depression. Brain NE and dopamine levels can be rapidly reduced by blocking synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). In the current investigation, AMPT was administered to drug-free depressed patients to evaluate the effect on mood of diminished catecholamine levels. Seventeen drug-free patients meeting DSM-III-R criteria for major depressive episode were tested with AMPT and an active placebo control, diphenhydramine. Testing was accomplished in a double-blind, crossover fashion, with random assignment to test conditions. Each test included baseline evaluation, 2 days with administration of either AMPT or diphenhydramine, and a follow-up day. Diphenhydramine was used as an active control because of the significant sedation associated with AMPT. Behavioral ratings, including visual analogue scales for a variety of feeling states, the Hamilton Depression Rating Scale (HDRS), and plasma for 3-methoxy-4-hydroxyphenelethyleneglycol (MPHG) and homovanillic acid (HVA) levels, were obtained. AMPT significantly reduced plasma HVA by 70% and MHPG by 50%, but it had no significant effects on the HDRS. AMPT also significantly increased visual analogue ratings of "tired" and decreased ratings of "energetic." Diphenhydramine significantly decreased HDRS scores, but the change was small and was not clinically apparent. The lack of AMPT effects on depressed mood, in conjunction with a prior report that large reductions in plasma tryptophan do not systematically alter depressed mood, indicate that monoamine deficiency by itself is insufficient explanation of the cause of depression. The role of the noradrenergic system needs to be considered in relationship to the many other neurobiologic factors that could be involved in the pathophysiology of depression.

Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression.

BACKGROUND: Most hypotheses of the therapeutic mechanism of action of antidepressant drugs have focused on the role of the monoamines. We examined the effect of catecholamine depletion on antidepressant-induced remission. METHOD: The tyrosine hydroxylase inhibitor alpha-methylparatyrosine and the antihistamine diphenhydramine hydrochloride were administered, during separate test sessions, to depressed patients in remission maintained with either norepinephrine reuptake inhibitors (desipramine [n = 7] or mazindol [n = 2]) or serotonin reuptake inhibitors (fluoxetine hydrochloride [n = 9] or sertraline hydrochloride [n = 1]). Because of considerable sedation associated with alpha-methylparatyrosine testing, diphenhydramine was used as an active control rather than an inactive placebo. The effects of alpha-methylparatyrosine and diphenhydramine on depression, anxiety, and plasma catecholamine metabolites were assessed. RESULTS: alpha-Methylparatyrosine produced similar significant decreases in plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels in the treatment groups. alpha-Methylparatyrosine produced a robust increase in depressive symptoms on the Hamilton Depression Rating Scale, including depressed mood, decreased concentration, anhedonia, loss of interest, and feelings of worthlessness, helplessness, and hopelessness, in the desipramine-mazindol but not in the fluoxetine-sertraline group. Diphenhydramine had no effects on mood in either treatment group. CONCLUSIONS: The therapeutic effects of norepinephrine reuptake inhibitors, but not serotonin reuptake inhibitors, are reversed by catecholamine depletion. Considered with previous reports that serotonin depletion produces depressive relapses in patients in remission maintained with serotonin reuptake inhibitors, but not norepinephrine reuptake inhibitors, these findings suggest that antidepressants may not work via a single monoamine-related mechanism.

Effects of sleep deprivation on serotonin function in depression.

There is considerable evidence that antidepressant treatments enhance serotonin (5-HT) function. In order to evaluate whether sleep deprivation (SD) produces alterations in 5-HT function, the increase in prolactin (PRL) produced by intravenous tryptophan (TRP) was assessed in depressed patients following SD and undisturbed sleep (US). Eleven depressed patients received mood ratings and TRP infusions after either SD or US, 1 week apart. In five women, but not six men, the TRP-induced PRL rise was markedly enhanced after SD compared to US. Mood score changes were not significantly different between US and SD and there was no significant relationship of mood changes to the TRP induced PRL response. The data suggests that SD produces an increase in 5HT function in female depressed patients. The lack of identified SD-induced changes in 5-HT function in men may be due to lower sensitivity of the TRP-induced PRL rise in depressed men than women.

Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients.

OBJECTIVE: To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response. METHOD: Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebo-controlled cross-over study. After testing, they received open sequential antidepressant treatment. RESULTS: Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greater decrease in Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greater increase in Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvement were more likely to respond. CONCLUSIONS: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.

The use of tryptophan depletion to evaluate central serotonin function in depression and other neuropsychiatric disorders.

The results from these and other studies provide an opportunity to critically re-examine the role of brain monoamine function in the pathophysiology of depression and the mechanism of action of antidepressant drugs. The following observations are most salient: 1. Tryptophan depletion, which reduces brain serotonin function, reverses the therapeutic effects of specific serotonin reuptake inhibitors (SSRIs) but not drugs which potently inhibit noradrenaline reuptake. In contrast, depletion of noradrenaline and dopamine, as a consequence of AMPT administration, reverses the remission induced by noradrenaline (desipramine) and dopamine (mazindol) reuptake inhibitors, but not SSRIs. These data suggest that the efficacy of antidepressant drugs may not be due to a common mechanism involving a single monoamine system. SSRIs and noradrenaline reuptake inhibitors may work via primary actions on serotonin and noradrenaline function, respectively. Alternatively, these two classes of antidepressant drugs may exert their therapeutic properties by affecting the function of an, as yet, unknown neuronal system that is regulated by these monoamine systems; 2. In both drug-free depressed patients and healthy subjects, tryptophan depletion and AMPT do not produce marked alterations in depressed mood. These results suggest that alterations in serotonin, dopamine, and noradrenaline systems may not reflect the primary pathology causing depressive illness. An alternative explanation is that in depressed patients these systems are maximally dysfunctional such that further manipulations do not worsen depressive systems. 3. Clinical experience and the results from several controlled studies indicate that the efficacy of SSRIs and noradrenaline inhibiting drugs are approximately equal.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants.

Brain catecholamines can be rapidly reduced by inhibiting their synthesis with alpha-methyl-para-tyrosine (AMPT). In order to assess the role of catecholamines in antidepressant action AMPT challenges were administered in a double-blind, placebo-controlled, crossover fashion to 14 depressed patients having maintained a therapeutic antidepressant response for > or = 2 weeks (3 desipramine, 2 mazindol, 5 fluoxetine, 4 sertraline). Each patient participated in two challenges one week apart. Each challenge included a baseline, two days of either AMPT or diphenhydramine (active placebo), and a followup. Antidepressant drugs were continued throughout testing. The 3 desipramine- and 2 mazindol-responders had a rapid increase in depression score during AMPT but not placebo (diphenhydramine) challenge whereas only 1 of 9 selective serotonin reuptake inhibitor (SSRI)-treated patients did. The implication of this is that the antidepressant response to desipramine may be more acutely dependent on brain catecholamine content than the response to SSRIs. In the context of our previous work with tryptophan depletion, these results suggest that the neurobiological mechanisms underlying the antidepressant responses to different drugs involve alterations in the functioning of different neurotransmitter systems and reinforce the importance of changes in both the serotonin and catecholamine systems for successful antidepressant responses.

Acute tryptophan depletion: a method of studying antidepressant action.

Serotonin (5-HT) has been implicated in the pathophysiology of depressive syndromes and in the mechanism of antidepressant drug action. Rapid dietary depletion of tryptophan (TRP) provides a paradigm for studying the role of 5-HT in depressed patients. Drug-free depressed patients do not show mood changes during TRP depletion but about one third have a clinically apparent, transient improvement in mood on return to normal TRP intake. Depressed patients in clinical remission after 6 to 8 weeks of antidepressant therapy experience a transient depressive relapse during acute TRP depletion. The significance of these findings will be discussed. Tryptophan depletion in other psychiatric syndromes will also be reviewed.

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.

Rat cerebral cortical synaptoneurosomal membranes. Structure and interactions with imidazobenzodiazepine and 1,4-dihydropyridine calcium channel drugs.

Small angle x-ray scattering has been used to investigate the structure of synaptoneurosomal (SNM) membranes from rat cerebral cortex. Electron micrographs of the preparation showed SNM with classical synaptic appositions intact, other vesicles, occasional mitochondria, and some myelin. An immunoassay for myelin basic protein placed the myelin content of normal rat SNM at less than 2% by weight of the total membrane present. X-Ray diffraction patterns showed five diffraction orders with a unit cell repeat for the membrane of 71 to 78 A at higher hydration states. At lower hydration, 11 orders appeared; the unit cell repeat was 130 A, indicating that the unit cell contained two membranes. Electron density profiles for the 130-A unit cell were determined; they clearly showed the two opposed asymmetrical membranes of the SNM vesicles. SNM membrane/buffer partition coefficients (Kp) of imidazobenzodiazepine and 1,4-dihydropyridine (DHP) calcium channel drugs were measured; Kp's for DHP drugs were approximately five times higher in rabbit light sarcoplasmic reticulum than in SNM. Ro 15-1788 and the DHP BAY K 8644 bind primarily to the outer monolayer of vesicles of intact SNM membranes. Nonspecific equilibrium binding of Ro 15-1788 occurs mainly in the upper acyl chain of the bilayer in lipid extracts of SNM membrane.