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Therapeutic Application

Capturing the different health conditions that PAP may adress

Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial

December 9, 2014 / Depressive Disorders, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Background

NMDA receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and NMDA receptor antagonist, may also be a rapidly acting treatment for TRD.

Methods

In this blinded, placebo-controlled crossover trial 20 TRD patients were randomized to a 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). Primary endpoint was the change on HDRS-21 24 hours after treatment.

Results

Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) minutes at a median inspiratory concentration of 44% (37 – 45%, IQR). In two patients nitrous oxide treatment was briefly interrupted and in three discontinued. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared to placebo (mean HDRS-21difference at 2 hours: -4.8 points, 95% CI -1.8 to – 7.8 points, p= 0.002; at 24 hours: -5.5 points, 95% CI -2.5 to -8.5 points, p<0.001; comparison between nitrous oxide and placebo: p<0.001). Four patients (20%) had treatment response (reduction ≥50% on HDRS); three patients (15%) a full remission (HDRS ≤ 7 points) after nitrous oxide, compared to one patient (5%) and none after placebo (odds ratio [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][OR] for response 4.0, 95% CI 0.45 – 35.79; OR for remission 3.0, 95% CI 0.31 – 28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity.

Conclusions

This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with treatment-resistant depression.

Nagele, P., Duma, A., Kopec, M., Gebara, M. A., Parsoei, A., Walker, M., … & Conway, C. (2014). Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial. Biological Psychiatry. https://dx.doi.org/10.1016/j.biopsych.2014.11.016
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Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects

November 29, 2014 / LSD, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , , ,

Abstract

Background

After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans.

Methods

In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects.

Results

Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed.

Conclusions

In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K. H., Vollenweider, F. X., … & Liechti, M. E. (2014). Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects. Biological psychiatry. https://dx.doi.org/doi:10.1016/j.biopsych.2014.11.015
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A single infusion of ketamine improves depression scores in patients with anxious bipolar depression

November 14, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Objective

Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine’s ability to decrease symptoms of depression.

Methods

Thirty-six patients with anxious (n = 21) and non-anxious (n = 15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post-hoc analyses compared changes in the Montgomery–Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14 days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7.

Results

A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p > 0.28).

Conclusions

Both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.

Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Richards, E. M., & Zarate, C. A. (2014). A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar disorders. https://dx.doi.org/10.1111/bdi.12277

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Ketamine and other potential glutamate antidepressants

November 12, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

The need for rapid acting antidepressants is widely recognised. There has been much interest in glutamate mechanisms in major depressive disorder (MDD) as a promising target for the development of new antidepressants. A single intravenous infusion of ketamine, a N-methyl-d–aspartate (NMDA) receptor antagonist anaesthetic agent, can alleviate depressive symptoms in patients within hours of administration. The mechanism of action appears to be in part through glutamate release onto non-NMDA receptors including α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic receptors. However these are also reported effects on 5-HT, dopamine and intracellular effects on the mammalian target of rapamycin (mTOR) pathway. The effects of SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants may also involve alterations in NMDA function. The article reviews the effect of current antidepressants on NMDA and examines the efficacy and mechanism of ketamine. Response to ketamine is also discussed and comparison with other glutamate drugs including lamotrigine, amantadine, riluzole, memantine, traxoprodil, GLYX-13, MK-0657, RO4917523, AZD2066 and Coluracetam. Future studies need to link the rapid antidepressant effects seen with ketamine to inflammatory theories in MDD.

Dutta, A., McKie, S., & Deakin, J. W. (2014). Ketamine and other potential glutamate antidepressants. Psychiatry research, 225(1-2), 1-13. https://dx.doi.org/10.1016/j.psychres.2014.10.028

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Psilocybin and Obsessive Compulsive Disorder

November 11, 2014 / Anxiety Disorders / PTSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By /

Abstract

Obsessive Compulsive Disorder (OCD) is a psychiatric disorder with considerable morbidity and mortality. This condition disables many individuals and is often refractory to treatment. Research suggests that serotonin plays a role in OCD symptom reduction. We present a case of an individual who successfully used psilocybin, a serotonergic agent, to reduce the core symptoms of OCD for several years. Although not endorsing this form of treatment, we feel that the successful use of this agent highlights the role of serotonergic factors in OCD and the need for further, legitimate research into the value of psilocybin in the treatment of anxiety disorders.

Wilcox, J. A. (2014). Psilocybin and Obsessive Compulsive Disorder. Journal of psychoactive drugs, 46(5), 393-395. https://dx.doi.org/10.1080/02791072.2014.963754

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LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects

November 11, 2014 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Papers, Psychology, Publications / By / , ,

Abstract

Objective: A recently published study showed the safety and efficacy of LSD-assisted psychotherapy in patients with anxiety associated with life-threatening diseases. Participants of this study were included in a prospective follow-up.

Method: 12 months after finishing LSD psychotherapy, 10 participants were tested for anxiety (STAI) and participated in a semi-structured interview. A Qualitative Content Analysis (QCA) was carried out on the interviews to elaborate about LSD effects and lasting psychological changes.

Results: None of the participants reported lasting adverse reactions. The significant benefits as measured with the STAI were sustained over a 12-month period. In the QCA participants consistently reported insightful, cathartic and interpersonal experiences, accompanied by a reduction in anxiety (77.8%) and a rise in quality of life (66.7%). Evaluations of subjective experiences suggest facilitated access to emotions, confrontation of previously unknown anxieties, worries, resources and intense emotional peak experiences à la Maslow as major psychological working mechanisms. The experiences created led to a restructuring of the person’s emotional trust, situational understanding, habits and world view.

Conclusions: LSD administered in a medically supervised psychotherapeutic setting can be safe and generate lasting benefits in patients with a life-threatening disease. Explanatory models for the therapeutic effects of LSD warrant further study.

Gasser, P., Kirchner, K., & Passie, T. (2014). LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects. Journal of Psychopharmacology. https://dx.doi.org/10.1177/0269881114555249
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Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety

November 8, 2014 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Objective

Suicide is a psychiatric emergency. Currently, there are no approved pharmacologic treatments for suicidal ideation. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal ideation as well as depression and anxiety, but the dynamic between these symptoms is not known. The aim of this analysis was to evaluate whether ketamine has an impact on suicidal thoughts, independent of depressive and anxiety symptoms.

Methods

133 patients with treatment-resistant depression (major depressive disorder or bipolar I/II disorder) received a single subanesthetic infusion of ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAMA) focusing on 230 min post-infusion.

Results

At 230 min post-infusion, correlations between changes in suicidal ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to 19% in the variance of ideation change. Correlations with anxiety ranged from 0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine infusion was associated with significant reductions in suicidal ideation compared to placebo, when controlling for the effects of ketamine on depression (F1,587 = 10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004).

Conclusions

Improvements in suicidal ideation after ketamine infusion are related to, but not completely driven by, improvements in depression and anxiety. Investigation of the specific effects of ketamine on suicidal thoughts is warranted.

Ballard, E. D., Ionescu, D. F., Voort, J. L. V., Niciu, M. J., Richards, E. M., Luckenbaugh, D. A., … & Zarate, C. A. (2014). Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. Journal of psychiatric research, 58, 161-166. https://dx.doi.org/10.1016/j.jpsychires.2014.07.027

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Effects of ecstasy on cooperative behaviour and perception of trustworthiness: A naturalistic study

November 8, 2014 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Background: Acute recreational use of 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) can promote pro-social effects which may alter interpersonal perceptions.

Aims: To explore such effects, this study investigated whether acute recreational use of ecstasy was associated with changes in individual perception of trustworthiness of people’s faces and co-operative behaviours.

Method: An independent group, repeated measures design was used in which 17 ecstasy users were tested on the night of drug use (day 0) and again three days later (day 3); 22 controls were tested on parallel days. On each day, participants rated the trustworthiness of 66 faces, carried out three co-operative behaviour tasks (public good; dictator; ultimatum game) and completed mood self-ratings.

Results: Acute ecstasy use was associated with increased face trustworthiness ratings and increased cooperative behaviour on the dictator and ultimatum games; on day 3 there were no group differences on any task. Self-ratings showed the standard acute ecstasy effects (euphoria, energy, jaw clenching) with negative effects (less empathy, compassion, more distrust, hostility) emerging on day 3.

Conclusions: Our findings of increased perceived trustworthiness and co-operative behaviours following use of ecstasy suggest that a single dose of the drug enhances aspects of empathy. This may in turn contribute to its popularity as a recreational drug and potentially to its enhancement of the therapeutic alliance in psychotherapy.

Stewart, L. H., Ferguson, B., Morgan, C. J. A., Swaboda, N., Jones, L., Fenton, R., … & Curran, H. V. (2014). Effects of ecstasy on cooperative behaviour and perception of trustworthiness: A naturalistic study. Journal of Psychopharmacology, 28(11), 1001-1008. https://dx.doi.org/10.1177/0269881114544775

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M1 and M2 Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

November 8, 2014 / Depressive Disorders, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2−/− mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.

Witkin, J. M., Overshiner, C., Li, X., Catlow, J. T., Wishart, G. N., Schober, D. A., … & Felder, C. C. (2014). M1 and M2 Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine. Journal of Pharmacology and Experimental Therapeutics, 351(2), 448-456. https://dx.doi.org/10.1124/jpet.114.216804
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On the transmethylation hypothesis: stress, N,N-dimethyltryptamine, and positive symptoms of psychosis

November 2, 2014 / DMT, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / ,

Abstract

Past research suggests a relationship between stress and positive symptoms of psychosis. However, the biological substrate of this relationship remains unknown. According to the transmethylation hypothesis, schizophrenia could result from a biochemical disruption in the stress mechanism. This biochemical disruption would lead to the production of a substance that would account for the symptoms of psychosis. Moreover, some studies have tested endogenous N,N-dimethyltryptamine (DMT) in the context of the transmethylation hypothesis. Stress has been found to elevate DMT levels in rodents. Also, elevated DMT levels have been associated with positive features of psychosis in psychiatric patients. Additionally, healthy participants treated with exogenous DMT experience predominantly positive symptoms of psychosis. The present paper examines endogenous DMT as a possible biological mediator of the relationship between stress and positive symptoms of psychosis.

Grammenos, D., & Barker, S. A. (2014). On the transmethylation hypothesis: stress, N, N-dimethyltryptamine, and positive symptoms of psychosis. Journal of Neural Transmission, 1-7. https://dx.doi.org/10.1007/s00702-014-1329-5
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