OPEN Foundation

Depression

Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression.

May 1, 2015 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression.

Andrade, C. (2015). Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. The Journal of clinical psychiatry, 76(5), e628-31. https://dx.doi.org/10.4088/JCP.15f10026

Link to full text

MDMA for the treatment of mood disorder: all talk no substance?

May 1, 2015 / Depression, MDMA, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

Background: Unipolar depression is the third highest contributor to the global burden of disease, yet current pharmacotherapies typically take about 6 weeks to have an effect. A rapid-onset agent is an attractive prospect, not only to alleviate symptoms before first-line antidepressants display therapeutic action, but as a further treatment option in nonresponsive cases. It has been suggested that 3,4-methylene-dioxymethamphetamine (MDMA) could play a part in the treatment of depression, either as a rapid-onset pharmacological agent or as an adjunct to psychotherapy. Whilst these hypotheses are in keeping with the monoamine theory of depression and the principles surrounding psychotherapy, explicit experimental evidence of an antidepressant effect of MDMA has rarely been established.

Aims: To address the hypothesis surrounding MDMA as a rapid-onset antidepressant by examining pharmacological, psychological and behavioural studies. We consider whether this therapy could be safe by looking at the translation of neurotoxicity data from animals to humans.

Method: A literature review of the evidence supporting this hypothesis was performed.

Conclusions: The pharmacology of MDMA offers a promising target as a rapid-onset agent and MDMA is currently being investigated for use in psychotherapy in anxiety disorders; translation from these studies for use in depression may be possible. However, experimental evidence and safety analysis are insufficient to confirm or reject this theory at present.

Patel, R., & Titheradge, D. (2015). MDMA for the treatment of mood disorder: all talk no substance?. Therapeutic Advances in Psychopharmacology, 2045125315583786. https://dx.doi.org/10.1177/2045125315583786

Link to full text

Mania following use of ibogaine: A case series

April 14, 2015 / Addiction, Depression, Iboga / Ibogaine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Safety / By / , , ,

Abstract

BACKGROUND:

Ibogaine is a naturally occurring hallucinogen with postulated anti-addictive qualities. While illegal domestically, a growing number of individuals have sought it out for treatment of opiate dependence, primarily in poorly regulated overseas clinics. Existing serious adverse events include cardiac and vestibular toxicity, though ours is the first report of mania stemming from its use.

OBJECTIVES:

To report on a case series of psychiatric emergency room patients whose unregulated use of ibogaine resulted in mania in three patients with no prior diagnosis of bipolar illness.

METHODS:

Review and summarize charts of three cases. Relevant literature was also reviewed for discussion.

RESULTS:

Two cases of reported ibogaine ingestion for self-treatment of addictions, and one for psycho-spiritual experimentation resulted in symptoms consistent with mania. No prior reports of mania were found in the literature, and the literature suggests growing popularity of ibogaine’s use.

CONCLUSIONS:

The three cases presented demonstrate a temporal association between ibogaine ingestion and subsequent development of mania.

SCIENTIFIC SIGNIFICANCE:

In light of these cases, clinicians faced with a new onset mania may benefit from careful substance use and treatment history, specifically regarding opiates. In the vulnerable and often desperate addiction population, in particular, the number of patients seeking this treatment appears to be growing. We advise clinicians to be prepared for discussing the safety, efficacy, and paucity of good data regarding ibogaine with patients who may be considering its use.

Marta, C. J., Ryan, W. C., Kopelowicz, A., & Koek, R. J. (2015). Mania following use of ibogaine: A case series. The American Journal on Addictions. https://dx.doi.org/10.1111/ajad.12209
Link to full text

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

April 13, 2015 / Depression, Ketamine, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Iadarola, N. D., Niciu, M. J., Richards, E. M., Voort, J. L. V., Ballard, E. D., Lundin, N. B., … & Zarate, C. A. (2015). Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Therapeutic Advances in Chronic Disease. https://dx.doi.org/10.1177/2040622315579059
Link to full text

The use of ketamine as an antidepressant: a systematic review and meta-analysis

April 7, 2015 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

Objective

The current meta-analysis examines the effects of ketamine infusion on depressive symptoms over time in major depressive disorder (MDD) and bipolar disorder (BD).

Methods

Following a systematic review of the literature, data were extracted from 21 studies (n  = 437 receiving ketamine) and analysed at four post-infusion time points (4 h, 24 h, 7 days and 12–14 days). The moderating effects of several factors were assessed including: repeat/single infusion, diagnosis, open-label/participant-blind infusion, pre–post/placebo-controlled design and the sex of patients.

Results

Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days. For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days. The percentage of males was a predictor of antidepressant response at 7 days. Effect sizes for open-label and participant-blind infusions were not significantly different at any time point.

Conclusions

Single ketamine infusions elicit a significant antidepressant effect from 4 h to 7 days; the small number of studies at 12–14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis — 24 h for MDD and 7 days for BD. The majority of published studies have used pre–post comparison; further placebo-controlled studies would help to clarify the effect of ketamine over time.

Coyle, C. M., & Laws, K. R. (2015). The use of ketamine as an antidepressant: a systematic review and meta‐analysis. Human Psychopharmacology: Clinical and Experimental, 30(3), 152-163. https://dx.doi.org/10.1002/hup.2475
Link to full text

Current knowledge on the neurobiology of classical hallucinogens and their relevance for the treatment of mood and anxiety disorders

March 28, 2015 / Anxiety disorders / PTSD, Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Hallucinogenic substances have been used for millenia. Still, the scientific investigation into the effects and mechanisms of classical hallucinogens in humans has only commenced with the discovery of LSD by Albert Hofmann in 1943. In the 1960’s, there were more than a thousand clinical studies that reported promising therapeutic effects of LSD and psilocybin in psychiatric patients. Only recently, however, the neuropharmacological and neurobiological underpinnings of hallucinogenic drugs have undergone systematic investigations. Despite having different chemical structures, classical hallucinogens produce striking similar subjective and behavioral effects in both animals and humans. Activation of the serotonin 2A (5-HT2A) receptor is a core feature in hallucinogenic pharmacology. Recent neuroimaging studies have begun to elucidate the brain mechanisms underlying hallucinogen-induced changes of thought, perception, and mood. Among the many networks involved in hallucinogen-related states of consciousness, the prefrontal cortex and the limbic regions appear to be especially relevant to the putative antidepressant effects of classical hallucinogens. Furthermore, hallucinogens may foster neuroplastic adaptations within cortico-subcortical brain networks. This appears to be a promising mechanism with regard to future clinical studies into the effects of classical hallucinogens in depression and anxiety.

Kraehenmann, R. (2015). The Effect of Serotonin Receptor Manipulation On Brain Networks and Its Impact On Emotion Regulation. European Psychiatry, 30, 21. http://dx.doi.org/10.1016/S0924-9338(15)30016-X
Link to full text

5HT2a Receptors – a New Target for Depression?

March 28, 2015 / Depression, LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Cortical 5HT2A receptors are largely expressed in layer 5 pyramidal neurons and appear to play a pivotal role in brain function in that they gate top-down descending inputs to local cortical microcircuits. There is evidence that they may play a role in depression in that the number of these receptors is increased in some people with depression and the augmenting action of atypical antipsychotics in depression is thought to be – at least in part – due to blockade of these receptors. We have explored this possibility by studying the effects of agonists at these receptors – the psychedelic drugs psilocybin and LSD. We found they had profound effects to reduce brain activity particularly in regions that higly express the 5HT2A receptor such as the default mode network [DMN]. As this region is overactive in depression this may explain the improvements in mood that users of psychedelic often report. Based on these findings a study of psilocybin in resistant depression has been funded by the UK MRC and will start in early 2015.

Nutt, D. (2015). 5HT2a Receptors–a New Target for Depression? European Psychiatry, 30, 35. http://dx.doi.org/10.1016/S0924-9338(15)30027-4
Link to full text

The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making

March 28, 2015 / Anxiety disorders / PTSD, Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

Social cognition is a crucial factor influencing development, progress, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. In particular, patients suffering from depression show an increased negative reaction to social exclusion and deficits in empathy. The 5HT-1A/2A receptor agonist psilocybin has previously been shown to reduce the neural response to negative emotional stimuli. However, it is not known if this extends to negative social interaction and whether 5HT-1A/2A receptor stimulation induces changes in empathy. Given the clear need for improved treatment of socio-cognitive functioning in psychiatric disorders, it is important to better understand the neuronal and neuromodulatory substrates of social cognition.

In a double-blind, randomized, cross-over design we therefore investigated the neural response to ostracism after the acute administration of psilocybin (0.215mg/kg) and placebo in healthy volunteers using fMRI. Furthermore, we assessed cognitive and emotional empathy using the Multifaceted Empathy Test.

The neural response to social exclusion in the ACC – a brain region associated with ‘social pain”- was reduced after psilocybin administration compared to placebo. Furthermore, emotional empathy was enhanced after treatment with psilocybin while no significant differences were found in cognitive empathy.

These results show that the 5HT-1A/2A receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits in psychiatric disorders. In particular, they may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in depressed patients.

Preller, K. H., Pokorny, T., Krähenmann, R., Dziobek, I., Stämpfli, P., & Vollenweider, F. X. (2015). The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making. European Psychiatry, 30, 22. http://dx.doi.org/10.1016/S0924-9338(15)30017-1
Link to full text

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

March 20, 2015 / Anxiety disorders / PTSD, Ayahuasca, Depression, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Objectives

Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode.

Methods:

Open-label trial conducted in an inpatient psychiatric unit.

Results:

Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement.<

Conclusions:

These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder.

Osório, F. D. L., Sanches, R. F., Macedo, L. R., Dos Santos, R. G., Maia-de-Oliveira, J. P., Wichert-Ana, L., … & Hallak, J. E. (2015). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Revista Brasileira de Psiquiatria, 37(1), 13-20. http://dx.doi.org/10.1590/1516-4446-2014-1496
Link to full text

Psychedelics not linked to mental health problems or suicidal behavior: A population study

March 5, 2015 / Addiction, Anxiety disorders / PTSD, Cacti / Mescaline, Depression, HPPD, LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychosis, Publications, Safety / By / ,

Abstract

A recent large population study of 130,000 adults in the United States failed to find evidence for a link between psychedelic use (lysergic acid diethylamide, psilocybin or mescaline) and mental health problems. Using a new data set consisting of 135,095 randomly selected United States adults, including 19,299 psychedelic users, we examine the associations between psychedelic use and mental health. After adjusting for sociodemographics, other drug use and childhood depression, we found no significant associations between lifetime use of psychedelics and increased likelihood of past year serious psychological distress, mental health treatment, suicidal thoughts, suicidal plans and suicide attempt, depression and anxiety. We failed to find evidence that psychedelic use is an independent risk factor for mental health problems. Psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use; serious adverse events involving psychedelics are extremely rare. Overall, it is difficult to see how prohibition of psychedelics can be justified as a public health measure.

Johansen, P. Ø., & Krebs, T. S. (2015). Psychedelics not linked to mental health problems or suicidal behavior: A population study. Journal of Psychopharmacology. https://dx.doi.org/10.1177/0269881114568039
Link to full text

30 April - Q&A with Rick Strassman

REGISTER NOW!
X