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Depressive Disorders

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

January 27, 2017 / Ayahuasca, Depressive Disorders, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-Asberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0.019; Cohen’s d=0.98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0.04; at D7, p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d=0.84; D2: Cohen’s d=0.84; D7: Cohen’s d=1.49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4.95; p = 0.04; NNT = 2.66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M., Pessoa, J., … & Tofoli, L. (2017). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial. bioRxiv, 103531. 10.1101/103531
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Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion

January 23, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications / By / , ,

Abstract

New and encouraging findings regarding the use of ketamine for depression in the context of psychotic symptoms have been published by Pennybaker et al. (1). In their analysis, patients with bipolar disorder without a history of psychosis had a more robust response to ketamine, and patients with a history of psychosis had a significant response compared with placebo as well. Concerning dissociative symptoms, even though patients with a history of psychosis endorsed more symptoms, these were not maintained after a 40-minute period, and no full psychosis was induced in their sample.

da Frota Ribeiro, C. M., Sanacora, G., & Ostroff, R. (2017). Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion. Biological Psychiatry. 10.1016/j.biopsych.2017.01.012
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The fibrinolytic system: A new target for treatment of depression with psychedelics

January 23, 2017 / Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Current understanding of the neurobiology of depression has grown over the past few years beyond the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor (BDNF) to mature BDNF. ProBDNF activation could potentially be supressed by competition with fibrin for plasmin and tPA. High affinity binding of plasmin and tPA to fibrin could result in a decrease of proBDNF activation during brain inflammation leading to fibrosis further perpetuating depressed mood. There is a paucity of data explaining the possible role of the fibrinolytic system or aberrant extravascular fibrin deposition in depression. We propose that within the brain, an imbalance between tPA and urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) and neuroserpin favors the inhibitors, resulting in changes in neurogenesis, synaptic plasticity, and neuroinflammation that result in depressive behavior. Our hypothesis is that peripheral inflammation mediates neuroinflammation, and that cytokines such as tumor necrosis factor alpha (TNF-α) can inhibit the fibrinolytic system by up- regulating PAI-1 and potentially neuroserpin. We propose that the decrement of the activity of tPA and uPA occurs with downregulation of uPA in part involving the binding and clearance from the surface of neural cells of uPA/PAI-1 complexes by the urokinase receptor uPAR. We infer that current antidepressants and ketamine mitigate depressive symptoms by restoring the balance of the fibrinolytic system with increased activity of tPA and uPA with down-regulated intracerebral expression of their inhibitors. We lastly hypothesize that psychedelic 5-ht2a receptor agonists, such as psilocybin, can improve mood through anti- inflammatory and pro-fibrinolytic effects that include blockade of TNF-α activity leading to decreased PAI-1 activity and increased clearance. The process involves disinhibition of tPA and uPA with subsequent increased cleavage of proBDNF which promotes neurogenesis, decreased neuroinflammation, decreased fibrin deposition, normalized glial-neuronal cross-talk, and optimally functioning neuro-circuits involved in mood. We propose that psilocybin can alleviate deleterious changes in the brain caused by chronic stress leading to restoration of homeostatic brain fibrinolytic capacity leading to euthymia.

Idell, R. D., Florova, G., Komissarov, A. A., Shetty, S., Girard, R. B. S., & Idell, S. (2017). The fibrinolytic system: A new target for treatment of depression with psychedelics. Medical Hypotheses, 100, 46-53. 10.1016/j.mehy.2017.01.013
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Administration of ketamine for unipolar and bipolar depression

January 18, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile.

METHODS: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science.

RESULTS: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included.

CONCLUSIONS: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine’s efficacy.

Kraus, C., Rabl, U., Vanicek, T., Carlberg, L., Popovic, A., Spies, M., … & Willeit, M. (2017). Administration of ketamine for unipolar and bipolar depression. International Journal of Psychiatry in Clinical Practice, 21(1), 2-12. 10.1080/13651501.2016.1254802
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Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature

January 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , ,

Abstract

Introduction: Over the past decade, ketamine has been studied for major depressive disorder and bipolar depression. Ketamine is believed to exert its antidepressant properties through N-methyl-D-aspartate receptor antagonism.

Methods: Study authors completed a literature review of seven randomized controlled trials of ketamine usage in major depressive disorder and bipolar depression.

Results: Ketamine demonstrated a statistically significant improvement over placebo or midazolam in major depressive disorder. Ketamine also exhibited a statistically significant improvement over placebo in bipolar depression.

Discussion: Ketamine has shown promise in quickly reducing symptoms in patients with treatment resistant depression and bipolar depression. Using ketamine may be helpful for patients that have exhausted other therapeutic options.

Grady, S. E., Marsh, T. A., Tenhouse, A., & Klein, K. (2017). Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature. Mental Health Clinician, 7(1), 16-23. 10.9740/mhc.2017.01.016

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Ayahuasca: An ancient sacrament for treatment of contemporary psychiatric illness?

January 1, 2017 / Ayahuasca, Depressive Disorders, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Ayahuasca is a traditional psychoactive sacrament that’s been used in Amazonian shamanic rituals for hundreds of years. Ayahuasca is notorious for its psychedelic properties produced from the combination of monoamine oxidase inhibitors (MAOIs) found in the Banisteriopsis caapi vine and N-N-dimethyltryptamine from Psychotria viridis or Diplopterys cabrerana. Recently, ritual use of ayahuasca has increased and garnered attention for its potential in treating mental illnesses, such as substance use and depressive disorders. Due to its MAOI properties, there are serious drug interactions that may be of concern among patients who participate in ayahuasca use. The objectives of this paper are to describe ayahuasca’s pharmacology, potential drug interactions, and clinical data for its treatment potential in psychiatric illness.

Malcolm, B. J., & Lee, K. C. (2017). Ayahuasca: An ancient sacrament for treatment of contemporary psychiatric illness?. Mental Health Clinician, 7(1), 39-45. 10.9740/mhc.2017.01.039

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Clinical potential of psilocybin as a treatment for mental health conditions

January 1, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Psilocybin, a classic hallucinogen, is a chemical produced by more than 100 species of mushrooms worldwide. It has high affinity for several serotonin receptors, including 5-HT1A, 5-HT2A, and 5-HT2C, located in numerous areas of the brain, including the cerebral cortex and thalamus. With legislation introduced in 1992, more work is being done to further understand the implications of psilocybin use in a number of disease states. Certain mental health disease states and symptoms have been studied, including depressed mood, anxiety disorders, obsessive-compulsive disorder, alcohol use disorder, and tobacco use disorder. This article provides an in-depth review of the study design and results of psilocybin in each of these conditions and discusses the clinical potential for use.

Daniel, J., & Haberman, M. (2017). Clinical potential of psilocybin as a treatment for mental health conditions. Mental Health Clinician, 7(1), 24-28. 10.9740/mhc.2017.01.024

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Ketamine Mechanism of Action: Separating the Wheat from the Chaff

January 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

Abstract

(R,S)-ketamine (ketamine) exerts rapid (within hours) and robust (>60% response) antidepressant effects in severely ill-depressed patients who have failed conventional treatments (Zarate et al, 2006). This clinical finding has been paradigm-shifting as there is now tremendous hope that very ill-depressed patients can be treated in a matter of hours, rather than many weeks or months required for standard therapies to take effect (if they do at all).

Gould, T. D., Zanos, P., & Zarate, C. A. (2017). Ketamine Mechanism of Action: Separating the Wheat from the Chaff. Neuropsychopharmacology, 42(1), 368-369. 10.1038/npp.2016.210
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Psilocybin: promising results in double-blind trials require confirmation by real-world evidence

December 6, 2016 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / ,

Breckenridge, A., & Grobbee, D. E. (2016). Psilocybin: promising results in double-blind trials require confirmation by real-world evidence. Journal of psychopharmacology (Oxford, England), 30(12), 1218. 10.1177/0269881116675784
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Psilocybin for depression and anxiety associated with life-threatening illnesses

December 6, 2016 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , ,

Abstract

Life-threatening and terminal illnesses are accompanied by substantial stressors that encumber both patients and their families. Faced with a life-threatening diagnosis such as late-stage cancer, these factors can compound the existential crisis of impending mortality and produce or exacerbate major depressive and anxiety symptoms (Silverstone, 1990; Vergo et al., 2016). Addressing depression and anxiety in the unique context of life-threatening illnesses has been a significant problem for palliative psychiatric care. In this regard, two recent studies suggest that the one-time use of the naturally derived psychoactive compound psilocybin could have the potential to alleviate these symptoms for up to six months.

McCorvy, J. D., Olsen, R. H., & Roth, B. L. (2016). Psilocybin for depression and anxiety associated with life-threatening illnesses. Journal of psychopharmacology (Oxford, England), 30(12), 1209. 10.1177/0269881116675771
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