Cerebrospinal fluid corticotropin-releasing hormone in healthy humans: effects of yohimbine and naloxone.

CRH neurons projecting from the paraventricular nucleus (PVN) of the hypothalamus to the median eminence control hypothalamic-pituitary-adrenal (HPA) axis activity. However, CRH neurons outside the PVN as well as PVN neurons projecting to sites other than the median eminence also contribute to the stress response and may play a role in mood and anxiety disorders. We have attempted to investigate possible noradrenergic and opioid regulation of these non-HPA CRH neurons. We hypothesized that yohimbine (an alpha2-adrenergic antagonist) would have stimulatory action on non-HPA CRH neurons, whereas naloxone (a mu-opioid receptor antagonist) would not have this effect. Adult normal volunteers received i.v. yohimbine (n = 5; 0.4 microg/kg), naloxone (n = 4; 125 microg/kg), or placebo (n = 3; 0.9% saline). Cerebrospinal fluid (CSF) was collected continuously, and concentrations of CSF CRH, CSF norepinephrine (NE), and plasma cortisol were measured. Administration of either yohimbine or naloxone caused significant increases in plasma cortisol concentrations over time. Although yohimbine robustly increased CSF NE levels and appeared to increase CSF CRH levels, these effects were not seen after naloxone or placebo administration. Intraindividual correlations were not observed between the measured concentrations of plasma cortisol and CSF CRH for any of the subjects. The results support the idea that CSF CRH concentrations reflect the activity of non-HPA CRH neurons. Although both yohimbine and naloxone stimulated the HPA axis, only yohimbine appeared to have stimulatory effects on central NE and non-HPA CRH.

Tryptophan depletion and risk of depression relapse: a prospective study of tryptophan depletion as a potential predictor of depressive episodes.

BACKGROUND: This study investigated the relationship between depressive symptom response during tryptophan depletion and future depressive episodes. METHODS: Twelve subjects with prior major depressive episodes in remission and medication-free for > or =3 months (patients), and 12 matched healthy (control) subjects received two tryptophan depletion tests 1 week apart. During follow-up the Hamilton Depression Rating Scale was administered weekly for 1 month, monthly for 3 months, and once at 6 and 12 months. RESULTS: With results from both tests, tryptophan depletion has a sensitivity of 78%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 86% to identify future depressive episodes. Survival analysis shows that mood response to tryptophan depletion reliably predicts major depressive episodes during the follow-up year (r =.2725, p =.014). CONCLUSIONS: Tryptophan depletion may be clinically useful in identifying individuals at risk for future major depressive episodes.

Antidepressant effects of ketamine in depressed patients.

BACKGROUND: A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. METHODS: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. RESULTS: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). CONCLUSIONS: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

Psychiatric research in the 21st century: opportunities and limitations.

The year 2000 prompts numerous prognostications of the events to occur during the next century. Except for the Y2K problem, the year 2000 is little different in substance than 1999 or 2001. However it is useful to use the occasion to consider where we have come from and where we are going. Thinking of the future will help clarify goals, define the problems, identify priorities, and outline pathways for progress.

Limited efficacy of ketoconazole in treatment-refractory major depression.

The authors examined the efficacy of ketoconazole in 16 adults with treatment-refractory major depressive disorder. Subjects participated in a 6-week, double-blind, placebo-controlled trial. Assessments of mood were made using the Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory (BDI), and the Clinical Global Impression Scale (CGI). Results showed that none of eight patients randomly assigned to receive placebo and two of eight patients randomly assigned to receive ketoconazole met criteria for response. As a group, patients assigned to receive ketoconazole showed no significant reductions in HAM-D, BDI, or CGI scores during the 6-week trial compared with those receiving placebo. These findings suggest a limited efficacy for ketoconazole in patients with treatment-refractory major depression.

Interactive effects of subanesthetic ketamine and haloperidol in healthy humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with prominent psychoactive effects in humans. This study evaluated whether the oral administration of haloperidol 5 mg would block the effects of an intravenous ketamine infusion (bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour). Twenty healthy subjects completed 4 test days involving the oral administration of haloperidol or matched placebo 2 h prior to the intravenous infusion of ketamine or saline. Ketamine produced cognitive, behavioral, neuroendocrine, and physiologic effects in the healthy subjects that were similar to previous reports. Haloperidol pretreatment reduced impairments in executive cognitive functions produced by ketamine as measured by proverb interpretations and the Wisconsin Card Sorting Test. However, it failed to block the capacity of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria in healthy subjects. These data outline an important, but functionally delineated modulation of ketamine effects by dopamine2 receptors and other sites of haloperidol action.

Tryptophan depletion and depressive vulnerability.

BACKGROUND: Rapid and transient depletion of tryptophan (TRP) causes a brief depressive relapse in most patients successfully treated with and taking selective serotonin reuptake inhibitors, but little change in drug-free, symptomatic depressed patients. This study investigates the effects of TRP depletion in drug-free subjects in clinical remission from a prior major depressive episode (MDE). METHODS: Twelve subjects with a prior MDE, currently in clinical remission and drug-free for at least 3 months (patients), and 12 healthy subjects without personal or family history of Axis I disorder (controls), received TRP depletion. The study was conducted in a double-blind, controlled [full (102-g) and quarter-strength (25 g) 15-amino acid drinks], crossover fashion. Behavioral ratings and plasma TRP levels were obtained prior to, during, and after testing. RESULTS: All subjects experienced significant depletion of plasma TRP on both test-drinks, showing a significant dose-response relation. Healthy control subjects had minimal mood changes, but patients had a depressive response of greater magnitude. CONCLUSIONS: In the context of prior TRP depletion studies with antidepressant-treated, and drug-free symptomatic depressed patients, these results suggest that depression may be caused not by an abnormality of 5-HT function, but by dysfunction of other systems or brain regions modulated by 5-HT.

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.

Transient depressive relapse induced by catecholamine depletion: potential phenotypic vulnerability marker?

BACKGROUND: Although state-related alterations in catecholamine function have been well-described in depressed subjects, enduring abnormalities have been less reliably identified. In our study, medication-free subjects with fully remitted major depression underwent a paradigm of catecholamine depletion, via use of the tyrosine hydroxylase inhibitor alpha-methylparatyrosine. METHOD: Subjects underwent 2 sets of testing conditions in a double-blind, random-ordered, crossover design, approximately 1 week apart. They underwent active catecholamine depletion (via oral administration of 5 g alpha-methylparatyrosine) or sedation-controlled, sham catecholamine depletion (via oral administration of 250 mg diphenhydramine hydrochloride), during a 2-day observation. Serial mood ratings and blood samples were obtained. RESULTS: Fourteen subjects completed the active testing condition; 13 completed sham testing. Subjects experienced marked, transient increases in core depressive and anxiety symptoms, as demonstrated by a mean 21-point increase on Hamilton Depression Rating Scale scores. Furthermore, 10 (71%) of 14 subjects fulfilled relapse criteria during active testing, whereas 1 (8%) of 13 subjects did so during sham testing. The severity of the depressive reaction correlated with baseline plasma cortisol levels (r = 0.59; P =.04). CONCLUSIONS: Euthymic, medication-free subjects with a history of major depression demonstrate significant depressive symptoms when undergoing testing with alpha-methylparatyrosine. This depressive reaction may represent a reliable marker for a history of depression. Further work is needed to clarify the significance of this finding.

Dark Agouti and Fischer 344 rats: differential behavioral responses to morphine and biochemical differences in the ventral tegmental area.

We sought to identify behavioral and biochemical differences between Dark Agouti and Fischer 344 inbred rat strains to assess whether they could serve as a model of genetically determined differences in sensitivity to drugs of abuse. We compared the strains for the following traits: morphine-induced locomotor activity and sensitization; circadian variation in plasma levels of corticosterone, a hormone reported to affect sensitivity to drugs of abuse; and several biochemical parameters in the ventral tegmental area and nucleus accumbens, brain regions implicated in the locomotor activating and reinforcing actions of drugs of abuse. Fischer 344 rats exhibited greater initial locomotor responses to morphine but, unlike Dark Agouti rats, did not develop sensitization to a second morphine exposure. Fischer 344 rats displayed a marked rise in basal plasma corticosterone levels in the late light phase and early dark phase, whereas Dark Agouti rats showed no significant circadian variation in corticosterone levels. Relative to drug-naive Fischer 344 rats, drug-naive Dark Agouti rats showed higher levels of tyrosine hydroxylase and glial fibrillary acidic protein, and lower levels of neurofilament proteins, in the ventral tegmental area. In contrast, no strain differences were found in levels of tyrosine hydroxylase, specific G protein subunits or protein kinase A in the nucleus accumbens. Together, these results demonstrate that Dark Agouti rats and Fischer 344 rats exhibit differences in specific behavioral, endocrine and biochemical parameters related to sensitivity to drugs of abuse.

Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized anxiety disorder.

In order to evaluate the effect of the CCK(B) antagonist CI-988 on behavioral, neuroendocrine, and physiologic responses to the mixed, post-synaptic serotonin (5-HT) agonist/antagonist mCPP, 16 patients with a principal DSM-III-R diagnosis of generalized anxiety disorder (GAD) were enrolled in a study that involved two challenge tests. On one day, patients received a single oral dose of CI-988 followed 30 min later by an i.v. infusion of 0.1 mg/kg mCPP. On a second test day patients received placebo CI-988 followed 30 min later by active i.v. mCPP. The sequence of CI-988 was randomly assigned and the testing was conducted in double-blind fashion. In an initial dose-finding phase (N = 6) with a dose of CI-988 of 25 mg, there were no significant between-test differences in behavioral response to mCPP. Accordingly, the second phase of the study was conducted with a CI-988 dose of 100 mg in another of patients (N = 10). CI-988 (100 mg) was well tolerated and had no significant effects on pretest anticipatory anxiety. There was no significant blunting of the anxiety response to mCPP as a result of CI-988 administration, nor did CI-988 affect physiologic or neuroendocrine measures. Correlations between peak changes in plasma levels of CI-988 and mCPP-induced anxiety in the high-dose patient group were not significant. Overall, these findings did not provide evidence of anxiolytic effects of CI-988 in patients with GAD. The lack of effect of CI-988 on neuroendocrine and physiological measures further suggests that CI-988's pharmacological effects could be independent of 5-HT function. However, follow-up studies using higher doses of CI-988 are indicated to confirm this preliminary finding as are studies more closely evaluating the interrelationship between CCK and 5-HT function in GAD.

Lithium and desipramine versus desipramine alone in the treatment of severe major depression: a preliminary study.

Improvement following lithium augmentation is well-documented in depressed patients resistant to tricyclic antidepressants. However, response latency to lithium augmentation is extremely variable, suggesting other mechanisms may be involved. To evaluate whether long-term tricyclic treatment is necessary for lithium augmentation's effect, the rapidity and magnitude of response to lithium combined with desipramine from the start of treatment was compared to desipramine alone in severely depressed patients. Patients with DSM-III-R major depression were randomized to double-blind, placebo-controlled treatment with either lithium + desipramine or placebo + desipramine for 4 weeks. Response criteria were based on Hamilton Depression Rating Scale scores and global improvement. Analysis of covariance of Hamilton scores demonstrated that lithium + desipramine was superior to placebo + desipramine at week 1 (P < 0.009), week 2 (P < 0.028), and week 3 (P < 0.07), although not at week 4. There were more responders to the combination than to monotherapy (P < 0.042). These preliminary data suggest that lithium + desipramine may have some efficacy in severely depressed patients. Further studies with larger samples are needed to confirm these findings.

Genetic analysis of behavioral, neuroendocrine, and biochemical parameters in inbred rodents: initial studies in Lewis and Fischer 344 rats and in A/J and C57BL/6J mice.

Previous work has identified inherent behavioral, neuroendocrine, and biochemical differences among inbred rodent strains that have been related to the animals' differential responsiveness to drugs of abuse or stress. In the present study, we sought to determine (1) whether there are genetic correlations among particular phenotypic traits that differ between a pair of inbred rat strains (Lewis and Fischer 344) or a pair of inbred mouse strains (A/J and C57BL/6J); (2) which of these traits might be amenable to quantitative trait locus analysis; and (3) whether additional behavioral or biochemical differences relevant to drug- or stress-responsiveness could be identified in these strains. Specifically, we measured several behavioral, neuroendocrine, and biochemical traits in parental Lewis and Fischer 344 rats and in 298 members of an F2 intercross population, as well as in parental A/J and C57BL/6J mice and in 11 of the AXB/BXA recombinant inbred mouse strains. Traits measured included exploratory locomotor activity in a novel environment; amphetamine-induced locomotor activity; several specific protein levels in striatal regions, including inhibitory G protein subunits, the dopamine transporter, the Fos family member transcription factor DeltaFosB, and the protein phosphatase inhibitor DARPP-32; and late-afternoon plasma corticosterone concentrations. Each of the traits measured in F2 rats or recombinant inbred mice appears to be influenced by multiple genes, as well as by environmental factors. There were statistically significant, albeit relatively weak, correlations among several traits in an F2 intercross population bred from Lewis and Fischer rats. Among the traits studied in Lewis and Fischer rats, one seemed most amenable to quantitative trait locus analysis: the level of the inhibitory G-protein subunit, Galphai, in the nucleus accumbens. We also found a robust genetic correlation between levels of DeltaFosB and levels of the dopamine transporter in striatal regions in AXB/BXA recombinant inbred mouse strains. While these studies demonstrate the likely complexity of the genetic factors that influence the numerous phenotypes associated with altered responsiveness to drugs of abuse and stress, they represent an initial and necessary step toward identifying specific genetic factors involved.

Tryptophan depletion during continuous CSF sampling in healthy human subjects.

The tryptophan (TRP) depletion paradigm has been employed to investigate mood and behavioral effects of acutely lowering plasma TRP, and presumably brain serotonin (5-hydroxytryptamine [5-HT]) levels through administration of a special diet and/or amino acid drink. Our goal was to test the assumption that a corresponding fall in central levels of TRP and 5-HT (measured by its major metabolite, 5-hydroxyindoleacetic acid [5-HIAA]) occurs during the standard execution of this method in healthy adult subjects. Three males and two females completed the protocol, which included a one-day low-TRP diet and a TRP-free amino acid drink. Lumbar puncture was performed, with placement of an indwelling catheter connected to a peristaltic pump and fraction collector. Cerebrospinal fluid (CSF) was sampled continuously for a 13.5-hour period (before, during, and after the drink), with fractions removed every 15 minutes. Plasma samples were simultaneously obtained. CSF TRP levels and plasma TRP levels were highly correlated, falling a mean of 92% and 85% from baseline, respectively. CSF nadirs were reached several hours after plasma nadirs. CSF 5-HIAA decreased modestly (24% to 40%, mean 31% change from baseline), with lowest concentrations observed 8-12 hours after the amino acid drink. These data suggest that TRP depletion results in substantial declines in central 5-HT turnover.

Naltrexone augmentation of neuroleptics in schizophrenia.

This study was conducted to determine whether the addition of naltrexone to ongoing neuroleptic treatment would facilitate the reduction in positive or negative symptoms in patients with schizophrenia. Twenty-one patients meeting DSM-III criteria for schizophrenia were enrolled; all patients had been stabilized for at least 2 weeks on their dosage of neuroleptic medicine before entering the study. Patients were randomized to receive either placebo or naltrexone 200 mg/day for 3 weeks in addition to their neuroleptic. Patients randomized initially into the placebo arm were crossed over to receive naltrexone in a single-blind fashion for 3 additional weeks. All patients were rated weekly with the Brief Psychiatric Rating Scale (BPRS). Fifteen patients received placebo and six received naltrexone in the first 3 weeks. No significant effects of naltrexone on total BPRS scores or BPRS subscale scores were observed. Patients who received naltrexone on a single-blind basis at the end of the placebo-controlled trial demonstrated a transient exacerbation in negative symptoms as reflected by the total BPRS score and the BPRS Withdrawal-Retardation subscale score. Repeated-measures analysis of variance (ANOVA) on the BPRS total score of the subsequent treatment with naltrexone showed a trend for a significance in the drug by time effect. Repeated-measures ANOVA on the BPRS Withdrawal-Retardation subscale of the subsequent treatment with naltrexone showed a significant drug by time effect. The current data failed to indicate a clinical benefit when naltrexone was added to the neuroleptic regimen. Other potential applications of naltrexone in schizophrenia are addressed.

The neurobiology of tryptophan depletion in depression: effects of intravenous tryptophan infusion.

BACKGROUND: Previous work has suggested that acute depletion of the serotonin (5-HT) precursor tryptophan (TRP) causes transient compensatory changes in the 5-HT system that might be exploited for their antidepressant effects. In this study, neuroendocrine and mood responses to intravenous (i.v.) infusion of TRP were examined in order to evaluate central 5-HT function in depressed patients undergoing acute TRP depletion. METHODS: Thirty-eight drug-free patients with DSM-III-R major depression participated. Each patient underwent two randomized, double-blind TRP depletion tests, one sham and one active. At the estimated time of maximum TRP depletion, each patient received an i.v. infusion of TRP 100 mg/kg. Blood was obtained for serum cortisol, prolactin, and growth hormone. Mood was assessed using standardized rating scales. RESULTS: The cortisol response to i.v. TRP was significantly greater during TRP depletion than during sham depletion. Depressive symptoms showed a tendency to decrease after i.v. TRP following active, but not sham, TRP depletion. CONCLUSIONS: These findings are consistent with the present hypothesis and previous evidence that acute TRP depletion in drug-free depressed patients induces compensatory upregulation of postsynaptic 5-HT receptors. These changes are insufficient to serve as a means of effecting clinical improvement, but suggest that the antidepressant properties of rapid, marked manipulations of 5-HT function warrant further study.

Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

Neurobiology of tryptophan depletion in depression: effects of m-chlorophenylpiperazine (mCPP).

This study utilized neuroendocrine and mood responses to intravenous (i.v.) infusion of the serotonin (5-HT) agonist m-chlorophenylpiperazine (mCPP) to evaluate central 5-HT function in depressed patients undergoing acute tryptophan (TRP) depletion. Twenty-two drug-free patients with DSM-III-R major depression participated. Each patient underwent two randomized, double-blind TRP depletion tests, one sham and one active. At the estimated time of maximum TRP depletion, each patient received an i.v. infusion of mCPP 0.1 mg/kg. Blood was obtained for serum cortisol, prolactin, and growth hormone. Multiple rating scales were used to assess mood. The cortisol response to i.v. mCPP was significantly greater during TRP depletion than during sham depletion, and free plasma TRP was negatively correlated with the cortisol response during TRP depletion. These findings are consistent with the hypothesis that acute TRP depletion in drug-free depressed patients induces a compensatory up-regulation of postsynaptic 5-HT receptors, most likely of the 5-HT2A/2C subtype. Such changes suggest a mechanism by which acute and potent manipulations of 5-HT function in depressed patients could be used to effect rapid clinical improvement.