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Brain noradrenergic systems have been shown to be altered in opioid dependence and to mediate aspects of opioid withdrawal. Pre-clinical and clinical studies by others have shown that yohimbine, which increases noradrenergic activity, also increases both baseline and fear enhancement of the magnitude of the acoustic startle response (ASR). In a separate report from this experiment, it was shown that yohimbine produced opioid withdrawal-like symptoms, including anxiety, in clinically stable methadone-maintained patients and also produced elevations in the norepinepherine (NE) metabolite, 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol serum levels. The current study reports the effects of intravenous yohimbine hydrochloride, 0.4 mg/kg versus saline (double-blind), on ASR magnitude, plasma MHPG, and cortisol levels in eight methadone-maintained patients and 13 healthy subjects in a double-blind fashion. Yohimbine increased startle magnitude in both groups. There was no basal (placebo day) difference between the startle response of the two groups, but methadone patients had a larger startle magnitude increase in response to yohimbine than healthy controls. Methadone-maintained patients had lower baseline plasma levels of MHPG and similar baseline plasma cortisol levels compared with normal subjects. Yohimbine caused significant elevation in cortisol and MHPG in both groups. Methadone-maintained subjects had higher elevations in cortisol levels and MHPG (methadone main effect) levels in response to yohimbine. However, when MHPG levels were corrected for baseline differences by analysis of covariance (ANCOVA), the yohimbine effect, but not the methadone effect remained statistically significant. These results are consistent with the previous report and support the hypothesis that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and of noradrenergic mechanisms of stress response persist in opioid-agonist maintenance. The ASR effect extends the previous report and provides an additional objective measure for perturbation of noradrenergic and stress responses in these patients.

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.

Background: Consistent with many studies demonstrating enhanced reactivity of the sympathetic nervous system in posttraumatic stress disorder (PTSD), the administration of yohimbine, a noradrenergic alpha(2)-antagonist, has been shown to increase core symptoms of PTSD and to induce greater increases in plasma 3-methyl-4-hydroxy-phenyl-glycol (MHPG) in subjects with PTSD compared with healthy control subjects. In turn, neuropeptide Y (NPY) has been shown to inhibit the release of norepinephrine from sympathetic noradrenergic neurons., Methods: In the following study, plasma NPY responses to yohimbine and placebo were measured in a subgroup of 18 subjects with PTSD and 8 healthy control subjects who participated in the previous study of the effect of yohimbine on plasma MHPG., Results: The PTSD subjects had lower baseline plasma NPY and blunted yohimbine-stimulated increases in plasma NPY compared with the healthy control subjects. Within the PTSD group, baseline plasma NPY levels correlated negatively with combat exposure scale scores, baseline PTSD and panic symptoms, and yohimbine-stimulated increases in MHPG and systolic blood pressure., Conclusions: This study suggests that combat stress-induced decreases in plasma NPY may mediate, in part, the noradrenergic system hyperreactivity observed in combat-related PTSD. The persistence of this decrease in plasma NPY may contribute to symptoms of hyperarousal and the expression of exaggerated alarm reactions, anxiety reactions, or both in combat veterans with PTSD long after war.

Background: Numerous laboratory-based studies have shown that chronic posttraumatic stress disorder (PTSD) is associated with alterations in catecholamines. In a recent neuroendocrine challenge study, IV yohimbine caused exaggerated subjective, behavioral, cardiovascular and catecholamine responses among combat veterans with PTSD compared to healthy controls. Yohimbine is an alpha-2-adrenergic receptor antagonist that activates noradrenergic neurons., Methods: This report describes the experience of 4 individuals with PTSD who took over-the-counter oral yohimbine that they had purchased from a health food store or pharmacy., Results: All 4 subjects experienced a marked exacerbation of anxiety/panic and PTSD-specific symptoms immediately after ingesting yohimbine in a natural setting., Conclusions: The response in these individuals closely resembled the response observed after IV yohimbine in combat veterans with PTSD. The present cases occurred in a natural setting and thus complement laboratory-based findings. The authors caution against the recreational or medical use of yohimbine in individuals who have PTSD.

Previous studies have shown that the intravenous administration of yohimbine, an alpha 2 antagonist, increases norepinephrine turnover and has related anxiogenic effects in humans. We herein report that yohimbine also increases plasma neuropeptide Y (NPY) in healthy human subjects. This finding is consistent with previous reports in animals, but contrasts with a previously reported study in humans. NPY is a 36 amino acid peptide neurotransmitter located in sympathetic and nonsympathetic nerve fibers, as well as in brain structures such as the locus coeruleus, where it is colocalized with norepinephrine. NPY has been shown to inhibit locus coeruleus neuronal firing, decrease norepinephrine release, and increase postsynaptic noradrenergic signal transduction. When administered centrally, NPY also has anxiolytic properties. This study therefore suggests that yohimbine challenge may be useful in assessing NPY and noradrenergic system interactions in neuropsychiatric disorders such as panic disorder or post traumatic stress disorder in which noradrenergic system dysfunction has been observed.

Preclinical studies suggest that acoustic startle amplitude is increased during ethanol withdrawal. The current study evaluated the effects of intravenous infusion of the alpha 2-adrenergic antagonist, yohimbine (0.4 mg/kg), the serotonin partial agonist m-chlorophenylpiperazine (mCPP, 0.1 mg/kg), and placebo administered to 22 male patients meeting DSM-III-R criteria for alcohol dependence and 13 male healthy subjects. Patients and healthy subjects completed 3 test days under double-blind conditions in a randomized order. Patients were sober for 12-26 days prior to testing. On each test day, participants completed startle testing 80 min following drug infusion. Stimuli with varying intensities (90, 96, 102, 108, 114 dB) were presented in a randomized order balanced across four blocks. Stimuli consisted of 40-ms bursts of white noise administered every 45-60 s for 15-20 min through headphones. Analyses indicated that patients exhibited elevated acoustic startle magnitudes on the placebo day relative to healthy subjects. In patients, the magnitude of startle amplitudes elicited at 90 dB, but not 114 dB, correlated significantly with the number of previous alcohol detoxifications. Yohimbine increased startle magnitudes and reduced startle latencies relative to placebo and mCPP in both patients and healthy subjects. mCPP did not alter startle magnitude in either group. Yohimbine also increased the probability that a 90-dB stimulus produced a startle response in healthy subjects, but not in patients. Blunting of yohimbine effects on startle probability may reflect the baseline elevations in startle probability levels in patients, but may also be consistent with other evidence of reduced postsynaptic, but not presynaptic, noradrenergic function in these same patients. These data replicate and extend previous reports indicating that yohimbine facilitates the acoustic startle response in humans. They also further implicate the number of episodes of ethanol withdrawal as a factor influencing subsequent neurobiological responsivity in chronic alcoholic patients. Based on the current data, future research should explore whether measurement of the acoustic startle response provides an objective quantitative severity measure of ethanol withdrawal.

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.

Objective: This study compared serotonergic (5-HT) and noradrenergic reactivity in recently detoxified alcoholic patients and healthy comparison subjects., Method: Participants were 22 male inpatients who met DSM-III-R criteria for alcohol dependence and who were abstinent for 12-26 days and 13 male healthy comparison subjects. Subjects completed 3 days of testing over 2 weeks under double-blind conditions that involved the intravenous infusions of m-chlorophenylpiperazine (mCPP), yohimbine, or a saline placebo. Drug effects on mood, physiologic responses, and plasma levels of cortisol, prolactin, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured., Results: Both mCPP and yohimbine infusion increased nervousness, vital signs, and plasma cortisol, prolactin, and MHPG levels relative to placebo Cortisol responses to mCPP were blunted in the alcoholic patients relative to the comparison subjects. Cortisol and prolactin responses to yohimbine were greater in the alcoholic patients, whereas their pulse increases after yohimbine infusion were blunted. No group differences emerged in MHPG, nervousness, or blood pressure responses to either drug., Conclusions: This study documents persistent alterations in neuroendocrine responsivity of both 5-HT and noradrenergic systems in alcoholic patients after detoxification. Blunted cortisol responses to mCPP in these recently detoxified patients may reflect reductions in 5-HT2 receptor function. The absence of altered MHPG responses to yohimbine in the alcoholic patients suggests that presynaptic noradrenergic responsivity is not persistently altered in these patients. In contrast, the enhanced cortisol responses and reduced pulse responses to yohimbine in alcoholic patients may reflect down-regulation of postsynaptic noradrenergic receptors.

There is considerable evidence that both the norepinephrine (NE) and serotonin (5-HT) systems are involved in the regulation of human anxiety and fear responses. To assess the modulating effects of central 5-HT levels on NE function, 11 healthy human subjects were studied with placebo-controlled challenge tests involving tryptophan depletion followed by administration of the alpha-2-adrenergic antagonist yohimbine 0.4 mg/kg IV. Five of the 11 subjects reported a marked increase in feelings of nervousness (> or = 25 mm on a 100 mm analog scale) following the combination test, while 1/11 had this response to yohimbine alone. No subjects had an increase in nervousness during other control tests. The increase in nervousness after the tryptophan depletion-yohimbine test was statistically significant for the whole group, but there were no other unique changes in behavioral, physiologic or biochemical (MHPG, cortisol) variables with this test. These data are discussed in terms of possible functional interactions between the 5-HT and NE neurotransmitter systems.

The effects of oral administration of ethanol [1.1 ml/kg 95% ethanol administered as a 20% (by volume) solution] and intravenous administration of the alpha 2 adrenergic receptor antagonist yohimbine hydrochloride (0.4 mg/kg), alone and in combination, were compared using a double-blind, placebo-controlled design. Twelve healthy subjects completed 4 test days during which drug effects on subjective measures of intoxication and anxiety, plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and cortisol, and cardiovascular indices were assessed. Acutely administered oral ethanol significantly increased the subjective measures of intoxication and anxiety, plasma MHPG, and sitting systolic blood pressure compared with placebo. Intravenous yohimbine significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and blood pressure relative to placebo. The ethanol-induced increase in plasma MHPG was significantly greater than that following yohimbine, whereas yohimbine resulted in significantly greater increases in anxiety, plasma cortisol, and blood pressure measurements than ethanol. The combined administration of ethanol and yohimbine had a clear additive effect of increasing the severity of acute intoxication compared with ethanol or yohimbine alone, and resulted in a significantly greater plasma MHPG response compared with either drug given alone. Although the pharmacokinetic effects of ethanol administration on NE metabolism must be considered, these findings suggest that the intoxicating and anxiogenic effects of acute ethanol administration may be associated with increased NE turnover, as measured by plasma MHPG, in healthy human subjects. In addition, these results indicate that ethanol and yohimbine may act additively to increase ethanol intoxication and that they may increase NE turnover through different physiological mechanisms.

Preclinical and clinical studies have suggested that the acoustic startle reflex (ASR) is a useful model to investigate the neurochemical basis of anxiety and fear states. This work has revealed that the anxiogenic alpha-2 receptor antagonist, yohimbine, increases the amplitude of the ASR in laboratory animals and in healthy human controls. Because of the growing body of data that support the hypothesis that severe stress results in substantial alterations in noradrenergic neuronal reactivity, the present investigation evaluated the effects of yohimbine on the ASR of 18 patients with PTSD and 11 healthy combat controls. Subjects received IV yohimbine (0.4 mg/kg) or saline placebo on 2 separate days in a randomized double blind placebo control design. A trial of two tone frequencies with varied intensity (90, 96, 102, 108, 114 dB) white noise and instantaneous rise time, was delivered binaurally through headphones. Tones were delivered every 25-60 s, for a 40-ms duration. Startle testing was performed 80 min post-infusion and lasted 15-20 min. Yohimbine significantly increased the amplitude, magnitude and probability of the ASR in combat veterans with PTSD, but did not do so in combat controls. Overall startle was significantly larger in the PTSD subjects; however, this did not account for the differential effect of yohimbine, since yohimbine had no significant effect in the control group. This study demonstrates an excitatory effect of yohimbine on the amplitude, magnitude and probability of the ASR in PTSD patients that is not seen in combat controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: This study evaluated the specificity of the ethanollike effects of the serotonergic receptor partial agonist m-chlorophenylpiperazine hydrochloride (MCPP) relative to the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the placebo in recently detoxified alcoholics. It also examined the relationship between ethanollike discriminative properties and the induction of craving in these patients. Both MCPP and yohimbine are anxiogenic in humans; thus, this study evaluated the role of anxiogenic and ethanollike effects in the elicitation of craving., Methods: Twenty-two male inpatients who met DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 12 to 26 days prior to the study completed 3 days of testing that involved the intravenous infusion of MCPP (0.1 mg/kg), (0.1 mg/kg), yohimbine hydrochloride (0.4 mg/kg), or a saline solution over 2 weeks under double-blind conditions. Ethanollike subjective effects were assessed using the Sensation Scale and visual analog scales to measure the degree of similarity to the effects of ethanol, cocaine, and marijuana. Five components of craving for alcohol were assessed using visual analog scales. The effects of the drugs on mood were assessed using visual analog scales. Plasma levels of cortisol, prolactin, and 3-methoxy-4-hydroxyphenylethyleneglycol were also measured during the test days., Results: m-Chlorophenylpiperazine and yohimbine produced significant increases compared with placebo in Sensation Scale scores and the visual analog scale score for nervousness. However, the effects of MCPP were rated as more similar to those of ethanol, cocaine, and marijuana than were those of either yohimbine or placebo. Also, MCPP but not yohimbine or placebo significantly increased craving for alcohol. Yohimbine and MCPP increased plasma prolactin and cortisol levels relative to placebo, whereas only yohimbine increased plasma 3-methoxy-4-hydroxyphenylethleneglycol levels., Conclusions: m-Chlorophenylpiperazine produced ethanollike effects and alcohol craving in recently detoxified alcoholics. Yohimbine increased Sensation Scale scores but was not recognized as ethanollike by patients. Although both drugs produced comparable levels of nervousness, yohimbine did not increase craving for alcohol. These data further implicate serotonergic systems in the discriminative properties of ethanol and may indicate a serotonergic contribution to craving. Noradrenergic systems contributed to the discriminative properties of ethanol but not to those features of ethanol response that were salient to craving in this population.

To assess the effects of the selective serotonin reuptake blocker fluvoxamine on noradrenergic function in patients with panic disorder, an intravenous yohimbine challenge test was administered to eight patients with panic disorder before and after 8 weeks of fluvoxamine treatment and to a parallel group of eight patients treated with placebo. Fluvoxamine treatment reduced yohimbine-induced anxiety while placebo treatment had no effect on this variable. Both fluvoxamine and placebo treatment had little effect on biochemical or physiologic responses to yohimbine.

Preclinical studies have suggested the acoustic startle reflex (ASR) may be a useful animal model to investigate the neurochemical basis of anxiety and fear states. This work has revealed that the anxiogenic alpha-2 receptor antagonist, yohimbine, increases the amplitude of the ASR in laboratory animals. The present investigation evaluated the effects of yohimbine on the ASR in healthy subjects. Seven healthy subjects received IV yohimbine (0.4 mg/kg) or saline placebo on two separate days in a randomized double blind placebo control design. A trial of 2 tone frequencies with varied intensity (90, 96, 102, 108, 114 dB) white noise, instantaneous rise time, was delivered binaurally through headphones. Tones were delivered every 25-60 sec, for a 30 ms duration. Startle testing was done 80 minutes post infusion and lasted 15-20 minutes. Sign rank testing indicated yohimbine caused an overall increase in startle amplitude, as well as significant augmentation of startle amplitude at 96, 102, 108, 114 decibels but not at the 90 dB intensity. Sign rank tests indicated a significant reduction of startle latency by yohimbine at only the 96 dB intensity. Significant correlations were observed between startle and peak anxiety, startle and plasma MHPG, peak anxiety and plasma MHPG. This study demonstrates in healty human subjects an excitatory effect of yohimbine on the magnitude of the ASR and a decrease in its latency. In the context of the key role of this reflex in the alarm response, this finding adds to the array of documented behavioral, biochemical and cardiovascular effects of yohimbine in humans which support the relationship between increased noradrenergic function and anxiety states.

In order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder, the behavioral, biochemical and cardiovascular effects of intravenous yohimbine (0.4 mg/kg) and clonidine (2 micrograms/kg) were determined in 15 healthy subjects and 38 patients with panic disorder. A subgroup of 24 panic disorder patients were observed to experience yohimbine-induced panic attacks and had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) than healthy subjects and other panic disorder patients. A blunted growth hormone response to clonidine and a significant clonidine-induced decrease in plasma MHPG was also observed in this subgroup of panic disorder patients. These data replicate and extend previous investigations, which are consistent with a large body of preclinical and human data relating increased noradrenergic neuronal function to human anxiety and fear states.

The effects of oral administration of the alpha 2 adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful alpha 2 antagonist in humans.

Three patients experienced yohimbine-induced manic symptoms. The authors discuss a possible neurobiological mechanism for this reaction to yohimbine.

Yohimbine (30 mg) produced significant increases in subjective anxiety, autonomic symptoms, blood pressure, and plasma 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) in ten healthy subjects. The effects of pretreatment with diazepam (10 mg) or clonidine (5 micrograms/kg) on these yohimbine induced changes was examined. Both diazepam and clonidine significantly antagonized yohimbine-induced anxiety, but only clonidine significantly attenuated the yohimbine induced increases in plasma MHPG, blood pressure, and autonomic symptoms. When given alone, clonidine significantly decreased plasma MHPG and blood pressure, whereas diazepam did not. These findings indicate that: (1) noradrenergic hyperactivity may be a factor in the production of some anxiety states; (2) the anti-anxiety effects of clonidine appear to result from its actions on receptors which decrease noradrenergic activity; (3) diazepam reverses yohimbine-induced anxiety without effects on several physiological or biochemical indicators of noradrenergic activity in humans.

There is extensive preclinical and clinical support for the hypothesis that hyperactivity of noradrenergic neuronal systems is related to the pathophysiology of some forms of human anxiety. In the present investigation, the behavioral, biochemical, and cardiovascular responses to the alpha 2-adrenergic receptor antagonist, yohimbine, was determined in 20 patients with generalized anxiety disorder (GAD) and 20 healthy subjects. The responses to yohimbine were generally similar in the two groups except there was a trend for the yohimbine-induced increase in plasma 3-methoxy-4-hydroxyphenylglycol to be less in the GAD patients. These findings contrast with previous studies of the effects of yohimbine in panic disorder patients and, thereby, support a neurobiological distinction between these two disorders.

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.

Administration of three oral doses of yohimbine (10 mg, 15 mg, 20 mg) to eight healthy subjects resulted in significant increases in plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). The 15 mg and 20 mg yohimbine doses induced modest increases in systolic blood pressure and autonomic symptoms such as piloerection and rhinorrhea. Marked behavioral effects such as anxiety were not observed. These results indicate that determination of the plasma MHPG response to yohimbine may be of value in assessing alpha 2 adrenergic autoreceptor function in humans.

The effect of single doses of alprazolam (1.5 mg) and yohimbine (30 mg) and alprazolam and yohimbine given together on plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), cortisol, blood pressure, and subjective behavioral ratings was studied in eight healthy subjects. In comparison to placebo, alprazolam significantly reduced plasma MHPG and cortisol, systolic and diastolic blood pressure, and increased subjective ratings of drowsiness and mellow. Yohimbine and the alprazolam-yohimbine combination significantly increased plasma free MHPG. Concomitant yohimbine administration antagonized the effects of alprazolam on blood pressure and attenuated alprazolam-induced changes in cortisol and subjective ratings. The ability of alprazolam to decrease plasma MHPG and blood pressure contrasts with previously reported effects of diazepam. The implications of the findings of the present investigation to the postulated role of brain noradrenergic function in the etiology of panic anxiety and the therapeutic mechanism of action of antipanic treatment are discussed.

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.

Preclinical investigations have shown that combined administration of the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the tricyclic antidepressant desipramine hydrochloride produces a reduction in brain beta-adrenergic receptor function within four days. Since the ability of antidepressant treatments to reduce beta-adrenergic receptor function has been hypothesized to mediate antidepressant efficacy, it was predicted that combined desipramine-yohimbine treatment would be a more rapid-acting and potent antidepressant regimen than desipramine alone. In the present investigation, the effects of desipramine (N = 11) and desipramine-yohimbine (N = 10) treatment on depressive symptoms, norepinephrine turnover, and blood pressure were determined in patients with major depression who had a history of nonresponse to standard antidepressant treatments. Neither desipramine nor desipramine-yohimbine proved to be an effective treatment, although concomitant yohimbine administration did attenuate the ability of desipramine to decrease plasma free and 24-hour urinary 3-methoxy-4-hydroxyphenyl-ethyleneglycol levels and blood pressure. Fifteen of the 21 patients eventually had a good response to pharmacologic treatments, particularly a desipramine-lithium carbonate or lithium carbonate-tranylcypromine sulfate combination treatment (11 of 14 responded). This study provides evidence against the beta-adrenergic receptor hypothesis of antidepressant action.