A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

RATIONALE: Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. OBJECTIVE: This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. METHODS: We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). RESULTS: Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders. CONCLUSION: These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.

Ethnic differences in physiological responses to fear conditioned stimuli.

The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders.

Increased fear-potentiated startle in major depressive disorder patients with lifetime history of suicide attempt.

BACKGROUND: Suicide is a common reason for psychiatric emergency and morbidity, with few effective treatments. Anxiety symptoms have emerged as potential modifiable risk factors in the time before a suicide attempt, but few studies have been conducted using laboratory measures of fear and anxiety. We operationally defined fear and anxiety as increased startle reactivity during anticipation of predictable (fear-potentiated startle) and unpredictable (anxiety-potentiated startle) shock. We hypothesized that a lifetime history of suicide attempt (as compared to history of no suicide attempt) would be associated with increased fear-potentiated startle. METHODS: A post-hoc analysis of fear- and anxiety-potentiated startle was conducted in 28 medication-free patients with Major Depressive Disorder (MDD) divided according to suicide attempt history. RESULTS: The magnitude of fear-potentiated startle was increased in depressed patients with lifetime suicide attempts compared to those without a lifetime history of suicide attempt (F(1,26)=5.629, p=.025). There was no difference in anxiety-potentiated startle by suicide attempt history. LIMITATIONS: This is a post-hoc analysis of previously analyzed patient data from a study of depressed inpatients. Further replication of the finding with a larger patient sample is indicated. CONCLUSIONS: Increased fear-potentiated startle in suicide attempters suggests the role of amygdala in depressed patients with a suicide attempt history. Findings highlight the importance of anxiety symptoms in the treatment of patients at increased suicide risk.

Major depression is not associated with blunting of aversive responses; evidence for enhanced anxious anticipation.

According to the emotion-context insensitivity (ECI) hypothesis, major depressive disorder (MDD) is associated with a diminished ability to react emotionally to positive stimuli and with blunting of defensive responses to threat. That defensive responses are blunted in MDD seems inconsistent with the conceptualization and diagnostic nosology of MDD. The present study tested the ECI hypothesis in MDD using a threat of shock paradigm. Twenty-eight patients with MDD (35.5±10.4 years) were compared with 28 controls (35.1±7.4 years). Participants were exposed to three conditions: no shock, predictable shock, and unpredictable shock. Startle magnitude was used to assess defensive responses. Inconsistent with the ECI hypothesis, startle potentiation to predictable and unpredictable shock was not reduced in the MDD group. Rather, MDD patients showed elevated startle throughout testing as well as increased contextual anxiety during the placement of the shock electrodes and in the predictable condition. A regression analysis indicated that illness duration and Beck depression inventory scores explained 37% (p<.005) of the variance in patients' startle reactivity. MDD is not associated with emotional blunting but rather enhanced defensive reactivity during anticipation of harm. These results do not support a strong version of the ECI hypothesis. Understanding the nature of stimuli or situations that lead to blunted or enhanced defensive reactivity will provide better insight into dysfunctional emotional experience in MDD.

Combining a dopamine agonist and selective serotonin reuptake inhibitor for the treatment of depression: a double-blind, randomized pilot study.

BACKGROUND: Antidepressants that act on two or more amine neurotransmitters may confer higher remission rates when first-line agents affecting a single neurotransmitter have failed. Pramipexole, a dopamine agonist, has antidepressant effects in patients with major depressive disorder (MDD). This pilot study examined the efficacy and safety of combination therapy with pramipexole and the selective serotonin reuptake inhibitor (SSRI) escitalopram in MDD. METHODS: In this double-blind, controlled, pilot study, 39 patients with DSM-IV MDD who had failed to respond to a standard antidepressant treatment trial were randomized to receive pramipexole (n=13), escitalopram (n=13), or their combination (n=13) for six weeks. Pramipexole was started at 0.375 mg/day and titrated weekly up to 2.25 mg/day; escitalopram dosage remained at 10 mg/day. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Subjects receiving pramipexole monotherapy had significantly lower MADRS scores than the combination group (p=0.01); no other primary drug comparisons were significant. The combination group had a substantially higher dropout rate than the escitalopram and pramipexole groups (69%, 15%, 15%, respectively). Only 15% of patients in the combination group tolerated regularly scheduled increases of pramipexole throughout the study, compared with 46% of patients in the pramipexole group. LIMITATIONS: Group size was small and the treatment phase lasted for only six weeks. CONCLUSIONS: The combination of an SSRI and a dopamine agonist was not more effective than either agent alone, nor did it produce a more rapid onset of antidepressant action. Combination therapy with escitalopram and pramipexole may not be well-tolerated.

Correlations between psychological tests and physiological responses during fear conditioning and renewal.

BACKGROUND: Anxiety disorders are characterized by specific emotions, thoughts and physiological responses. Little is known, however, about the relationship between psychological/personality indices of anxiety responses to fear stimuli. METHODS: We studied this relationship in healthy subjects by comparing scores on psychological and personality questionnaires with results of an experimental fear conditioning paradigm using a visual conditioned stimulus (CS). We measured skin conductance response (SCR) during habituation, conditioning, and extinction; subsequently testing for recall and renewal of fear 24 hours later. RESULTS: We found that multiple regression models explained 45% of the variance during conditioning to the CS+, and 24% of the variance during renewal of fear to the CS+. Factors that explained conditioning included lower levels of conscientiousness, increased baseline reactivity (SCL), and response to the shock (UCR). Low levels of extraversion correlated with greater renewal. No model could be found to explain extinction learning or extinction recall to the CS+. CONCLUSIONS: The lack of correlation of fear extinction with personality and neuropsychological indices suggests that extinction may be less determined by trait variables and cognitive state, and may depend more on the subject's current emotional state. The negative correlation between fear renewal and extraversion suggests that this personality characteristic may protect against post-treatment relapse of symptoms of anxiety disorders.