Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

BACKGROUND: Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. METHOD: We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. RESULTS: The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. CONCLUSIONS: The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

Cognitive control of attention is differentially affected in trauma-exposed individuals with and without post-traumatic stress disorder.

BACKGROUND: This study aimed to determine whether patients with post-traumatic stress disorder (PTSD) show difficulty in recruitment of the regions of the frontal and parietal cortex implicated in top-down attentional control in the presence and absence of emotional distracters. METHOD: Unmedicated individuals with PTSD (n = 14), and age-, IQ- and gender-matched individuals exposed to trauma (n = 15) and healthy controls (n = 19) were tested on the affective number Stroop task. In addition, blood oxygen level-dependent responses, as measured via functional magnetic resonance imaging, were recorded. RESULTS: Patients with PTSD showed disrupted recruitment of lateral regions of the superior and inferior frontal cortex as well as the parietal cortex in the presence of negative distracters. Trauma-comparison individuals showed indications of a heightened ability to recruit fronto-parietal regions implicated in top-down attentional control across distracter conditions. CONCLUSIONS: These results are consistent with suggestions that emotional responsiveness can interfere with the recruitment of regions implicated in top-down attentional control; the heightened emotional responding of patients with PTSD may lead to the heightened interference in the recruitment of these regions.

Battlefield-like stress following simulated combat and suppression of attention bias to threat.

BACKGROUND: Acute stress disorder involves prominent symptoms of threat avoidance. Preliminary cross-sectional data suggest that such threat-avoidance symptoms may also manifest cognitively, as attentional threat avoidance. Confirming these findings in a longitudinal study might provide insights on risk prediction and anxiety prevention in traumatic exposures. METHOD: Attention-threat bias and post-traumatic symptoms were assessed in soldiers at two points in time: early in basic training and 23 weeks later, during advanced combat training. Based on random assignment, the timing of the repeat assessment occurred in one of two schedules: for a combat simulation group, the repeat assessment occurred immediately following a battlefield simulation exercise, and for a control group, the assessment occurred shortly before this exercise. RESULTS: Both groups showed no threat-related attention bias at initial assessments. Following acute stress, the combat simulation group exhibited a shift in attention away from threat whereas the control group showed no change in attention bias. Stronger threat avoidance in the combat simulation group correlated with severity of post-traumatic symptoms. Such an association was not found in the control group. CONCLUSIONS: Acute stress may lead some individuals to shift their attention away from threats, perhaps to minimize stress exposure. This acute attention response may come at a psychological cost, given that it correlates with post-traumatic stress disorder (PTSD) symptoms. Further research is needed to determine how these associations relate to full-blown PTSD in soldier and civilian populations.

Attention bias away from threat during life threatening danger predicts PTSD symptoms at one-year follow-up.

BACKGROUND: Recent studies find a correlation between attentional threat avoidance under stress and posttraumatic stress symptoms. In this study, we assessed this association longitudinally in exposed and unexposed individuals. The degree of threat avoidance during exposure was expected to predict levels of posttraumatic stress symptoms 1 year later. METHODS: Thirty-two participants were recruited and followed for 12 months, including 18 subjects exposed to rocket attacks and 14 nonexposed subjects. At 1-year follow-up, participants completed self-reports and an attention dot-probe task assessing threat-related bias. RESULTS: State anxiety decreased at follow-up in exposed participants, though posttraumatic stress disorder (PTSD) and depression symptoms remained higher in exposed than in the nonexposed group. Attentional threat avoidance during imminent danger in the exposed group changed to threat attendance a year later, such that both the exposed and the nonexposed group exhibited similar threat bias patterns. As hypothesized, in the exposed group, stronger attentional threat avoidance during stress exposure predicted higher levels of PTSD symptoms 1 year later. CONCLUSIONS: Attention bias away from threat during acute stress may relate to risk for PTSD. This suggests that neurocognitive measures may index risk for PTSD.

The cellular neurobiology of depression.

Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression.

Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome.

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg-1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.

The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for chronic post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is psychiatric disease, which can occur following exposure to traumatic events. PTSD may be acute or chronic, and can have a waxing and waning course of symptoms. It has been hypothesized that proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) or plasma might be mediators of the psychophysiological mechanisms relating a history of trauma exposure to changes in behavior and mental health disorders, and medical morbidity. Here we test the cytokine/chemokine hypothesis for PTSD by examining levels of 17 classical cytokines and chemokines in CSF, sampled at 0900 hours, and in plasma sampled hourly for 24 h. The PTSD and healthy control patients are from the NIMH Chronic PTSD and healthy control cohort, initially described by Bonne et al. (2011), in which the PTSD patients have relatively low comorbidity for major depressive disorder (MDD), drug or alcohol use. We find that in plasma, but not CSF, the bivariate MCP4 (CCL13)/ MCP1(CCL2) ratio is ca. twofold elevated in PTSD patients compared with healthy controls. The MCP-4/MCP-1 ratio is invariant over circadian time, and is independent of gender, body mass index or the age at which the trauma was suffered. By contrast, MIP-1ß is a candidate biomarker for PTSD only in females, whereas TARC is a candidate biomarker for PTSD only in males. It remains to be discovered whether these disease-specific differences in circadian expression for these specific immune signaling molecules are biomarkers, surrogates, or drivers for PTSD, or whether any of these analytes could contribute to therapy.

Noradrenergic function and the mechanism of action of antianxiety treatment. II. The effect of long-term imipramine treatment.

Considerable preclinical and clinical evidence indicates that increased noradrenergic function is involved in the development of anxiety. Imipramine hydrochloride, which has complex effects on noradrenergic function in animals, is effective in patients with agoraphobia and panic disorder. To assess the effects of imipramine on noradrenergic function in patients, plasma levels of free 3-methoxy-4-hydroxyphenylglycol (MHPG) and yohimbine-induced increases in plasma MHPG levels, anxiety-nervousness, blood pressure, and somatic symptoms were studied before and during long-term imipramine treatment in 11 patients meeting DSM-III criteria for agoraphobia with panic attacks. Long-term imipramine treatment significantly decreased baseline plasma MHPG levels by 38% and modestly potentiated yohimbine-induced increases in blood pressure, but it did not alter yohimbine-induced increases in plasma MHPG levels or in patient ratings of anxiety-nervousness. The therapeutic effects of imipramine in panic disorder may relate more to the decrease in norepinephrine turnover than to alterations of alpha 2-adrenergic autoreceptor function.

Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment.

There is preclinical and clinical evidence suggesting that one neural mechanism responsible for antipanic efficacy is a reduction in brain noradrenergic function. Alprazolam, a triazolobenzodiazepine, has been demonstrated to have antipanic properties; however, to our knowledge, its effects on noradrenergic function have not been established. To assess whether alprazolam alters noradrenergic function, the effects of alprazolam on baseline plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and yohimbine-induced increases in plasma MHPG level, anxiety-nervousness, blood pressure, and somatic symptoms were studied in 14 patients with agoraphobia and panic disorder. Long-term alprazolam treatment significantly reduced plasma MHPG baseline and blunted the yohimbine-induced increases in plasma MHPG, anxiety-nervousness, and sitting systolic blood pressure. These observations suggest that the antipanic mechanism of action of alprazolam may be due in part to an interaction between benzodiazepine-sensitive and noradrenergic neural systems.

Primary affective disorder criteria and the endogenous-reactive distinction.

Seventy-six patients hospitalized during the course of one year with a depressive episode and without prior history of other psychiatric illness were evaluated retrospectively using the primary affective disorder criteria. Symptom ratings were made by two raters uninvolved in the treatment of the patient and blind to the discharge diagnosis, hospital course, and treatment response. The patients were designated "endogenous" or reactive" based on whether the depressive syndrome was autonomous or responsive to environmental changes. Ninety-two percent of the patients with endogenous depression and 45% of those with reactive depression met the criteria for definite primary affective disorder. We suggest that the primary affective disorder criteria define a heterogeneous group of patients with respect to the endogenous-reactive distinction. The value of criteria that would identify a homogeneous group with an endogenous depressive state is discussed. The primary affective disorder symptoms that did identify patients with endogenous depression were psychomotor change, self-reproach, and decreased concentration.

Alpha 2-adrenergic and opiate receptor blockade. Synergistic effects on anxiety in healthy subjects.

To evaluate interactions between the opiate and adrenergic systems in healthy humans, concomitant administration of the opiate antagonist, naloxone hydrochloride, and the alpha 2-adrenergic receptor antagonist, yohimbine hydrochloride, was compared with the administration of placebo and of each drug separately. A synergistic effect of the combination (larger than the sum of the effects of the two drugs separately) was observed on subject ratings of nervousness, anxiety, tremors, palpitations, nausea, hot and cold flashes, and increased plasma cortisol concentrations. In addition, following the combination, each of the male subjects studied reported a full penile erection lasting at least 60 minutes, an effect not reported when each drug was given separately. These results demonstrate that interactions between the opiate the adrenergic systems have important implications for our understanding of the cause and treatment of anxiety disorders and male impotence.

Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder.

Clonidine hydrochloride, an alpha 2-adrenergic receptor agonist that decreases noradrenergic function, was administered to 21 healthy subjects and 26 drug-free patients with agoraphobia and panic attacks. Clonidine produced significantly greater decreases in plasma MHPG levels and sitting and standing diastolic blood pressure and significantly smaller increases in growth hormone levels and self-rated drowsiness in the patients. These findings indicate that the regulation of noradrenergic activity is aberrant in some patients with panic disorder, since a previous study demonstrated that patients with panic disorder exhibit increased plasma MHPG levels, blood pressure, and behavioral responses to the alpha 2-adrenergic receptor antagonist yohimbine. The increased dynamic range of noradrenergic activity observed as an increased sensitivity to both clonidine and yohimbine may reflect abnormalities in the regulatory inputs to noradrenergic neurons, or dysfunction in the alpha 2-adrenergic receptor effector coupling mechanism or the intracellular effector system.

Serotonin function in panic disorders. The effect of intravenous tryptophan in healthy subjects and patients with panic disorder before and during alprazolam treatment.

Preclinical evidence suggests that alterations in serotonin function may relate to the development of anxiety and the therapeutic effectiveness of antianxiety treatments. Serotonin increases prolactin release, and intravenous administration of the serotonin precursor, tryptophan, produces reliable elevations in serum prolactin levels. To evaluate serotonergic function, the effects of intravenous tryptophan on prolactin secretion were determined in 23 drug-free patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder and 21 age- and sex-matched healthy subjects. In nine of the patients the tryptophan infusion was repeated during long-term alprazolam treatment. The ability of tryptophan to increase prolactin levels was not different between the patients and healthy subjects and was not altered by alprazolam treatment. These findings suggest serotonin function may be normal in panic anxiety disorders and the antipanic mechanism of action of alprazolam may be unrelated to effects on serotonin activity.

Major depression in patients with agoraphobia and panic disorder.

A review of the life-time occurrence of major depression, the temporal relationship of major depression to episodes of panic and agoraphobic disorders, and the severity of anxiety and depressive symptoms were determined in 60 patients with agoraphobia or panic disorder. Forty-one (68%) of the patients had a past or current episode of major depression, and 35 (85%) of these patients had endogenous-type major depression. Twenty patients (33%) had an episode of primary major depression, and an average of three years separated the end of primary major depression and the first panic attack. Secondary major depression occurred in 28 patients. Patients with a history of major depression had a more severe anxiety disorder. These data support the view that in a subgroup of patients, episodes of depression and panic anxiety disorder may be manifestations of a common underlying pathogenic process.

Noradrenergic function in panic anxiety. Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder.

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 20 healthy subjects and 39 drug-free patients with agoraphobia and panic attacks. Following drug administration, changes in plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), BP, pulse rate, and subjective ratings of feelings and somatic symptoms were examined during a four-hour period. Yohimbine produced significantly greater increases in patient-rated anxiety, nervousness, palpitations, hot and cold flashes, restlessness, tremors, piloerection, and sitting systolic BP in the total patient group compared with healthy subjects. There were significant correlations between the yohimbine-induced rise in plasma MHPG level and patient-rated anxiety and nervousness and the frequency of reported panic attacks. Patients experiencing frequent panic attacks (greater than 2.5 per week) had a significantly greater plasma MHPG response to yohimbine than the healthy subjects and patients having less frequent panic attacks. These observations support a hypothesis of increased sensitivity to augmented noradrenergic function in anxiety states associated with panic, and they suggest that impaired presynaptic noradrenergic neuronal regulation may exist in patients with frequent panic attacks.

Agoraphobia with panic attacks. Development, diagnostic stability, and course of illness.

A structured psychiatric interview was used to examine the symptom history of 55 patients meeting DSM-III criteria for agoraphobia with panic attacks and five patients meeting DSM-III criteria for panic disorder. Anticipatory anxiety and generalized anxiety occurred in over 80% of the patients, and these anxiety states together with panic attacks and phobic avoidances had courses that were chronic and unremitting. Major depression occurred in 70% of the patients and had an episodic course that differentiated it from the anxiety states. Other frequently reported disorders were childhood separation disorder (18%), alcoholism (17%), and obsessive compulsive disorder (17%). An initial nonspontaneous first panic attack and separation anxiety was associated with earlier onset and longer duration of agoraphobia and panic disorder. An inaccurate cognitive appraisal of the initial panic attack frequently led to the rapid development of subsequent agoraphobia. Caffeine consumption exacerbated anxiety in 54% of the patients and triggered panic attacks in 17%. Fifty-one percent of female agoraphobics experienced premenstrual exacerbation of anxiety symptoms.

Noradrenergic function in schizophrenia.

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 16 healthy subjects and 18 drug-free schizophrenic patients with (n = 10) and without (n = 8) tardive dyskinesia (TD). Outcome measures of this double-blind, placebo-controlled study included changes in behavior, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) level, blood pressure, and heart rate. A subgroup of six patients experienced a notable dysphoric arousal reaction that occurred 60 to 90 minutes following administration of 20 mg of yohimbine, this reaction was not observed in healthy subjects. The schizophrenic group as a whole (not the subgroup) showed a statistical trend toward a greater yohimbine-induced increase in plasma MHPG level and systolic sitting blood pressure. The patients with TD did not differ from those without TD or from healthy controls in their response to yohimbine. These results do not support the hypothesis that noradrenergic dysfunction plays a strong central role in the pathogenesis of schizophrenia or TD. However, further studies of noradrenergic dysfunction in sub-groups of patients with schizophrenia are indicated.

Increased anxiogenic effects of caffeine in panic disorders.

The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages.

Serotonin function and mechanism of action of antidepressant treatment. Effects of amitriptyline and desipramine.

The effects of amitriptyline hydrochloride and desipramine hydrochloride treatment on brain serotonin (5-HT) function were investigated in 21 patients. The ability of an intravenous infusion of the serotonin precursor tryptophan to raise serum prolactin (PRL) levels was determined in 13 depressed patients during placebo administration and after 28 to 35 days of treatment with either amitriptyline or desipramine. Both desipramine (N = 7) and amitriptyline (N = 6) significantly increased the PRL rise induced by tryptophan compared with a preceding placebo period. In contrast, following long-term amitriptyline and desipramine treatment, the ability of tryptophan to increase PRL was enhanced two weeks following abrupt cessation of amitriptyline therapy (N = 5), but not after discontinuation of desipramine therapy. The results of this investigation are consistent with electrophysiologic and behavioral studies in laboratory rats and suggest that desipramine- and amitriptyline-induced alterations in 5-HT function may be related to their antidepressant mechanism of action.