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Psychology

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

May 1, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, 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

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

May 1, 2015 / Depressive Disorders, MDMA, Neuroscience, Papers, Psychology, 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

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Intimate insight: MDMA changes how people talk about significant others

April 28, 2015 / MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

Rationale: ±3,4-methylenedioxymethamphetamine (MDMA) is widely believed to increase sociability. The drug alters speech production and fluency, and may influence speech content. Here, we investigated the effect of MDMA on speech content, which may reveal how this drug affects social interactions.

Method: Thirty-five healthy volunteers with prior MDMA experience completed this two-session, within-subjects, double-blind study during which they received 1.5 mg/kg oral MDMA and placebo. Participants completed a five-minute standardized talking task during which they discussed a close personal relationship (e.g. a friend or family member) with a research assistant. The conversations were analyzed for selected content categories (e.g. words pertaining to affect, social interaction, and cognition), using both a standard dictionary method (Pennebaker’s Linguistic Inquiry and Word Count: LIWC) and a machine learning method using random forest classifiers.

Results: Both analytic methods revealed that MDMA altered speech content relative to placebo. Using LIWC scores, the drug increased use of social and sexual words, consistent with reports that MDMA increases willingness to disclose. Using the machine learning algorithm, we found that MDMA increased use of social words and words relating to both positive and negative emotions.

Conclusions: These findings are consistent with reports that MDMA acutely alters speech content, specifically increasing emotional and social content during a brief semistructured dyadic interaction. Studying effects of psychoactive drugs on speech content may offer new insights into drug effects on mental states, and on emotional and psychosocial interaction.

Baggott, M. J., Kirkpatrick, M. G., Bedi, G., & de Wit, H. (2015). Intimate insight: MDMA changes how people talk about significant others. Journal of Psychopharmacology, 0269881115581962. https://dx.doi.org/10.1177/0269881115581962
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Ketamine-A Narrative Review of Its Uses in Medicine

April 24, 2015 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Psychology, Publications / By / , , , ,

Abstract

One of the most fascinating drugs in the anesthesiologist’s armament is ketamine, an N-methyl-D-aspartate receptor antagonist with a myriad of uses. The drug is a dissociative anesthetic and has been used more often as an analgesic in numerous hospital units, outpatient pain clinics, and in the prehospital realm. It has been used to treat postoperative pain, chronic pain, complex regional pain syndrome, phantom limb pain, and other neuropathic conditions requiring analgesia. Research has also demonstrated its efficacy as an adjunct in psychotherapy, as a treatment for both depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and neurologic conditions. Ketamine is not without its adverse effects, some of which can be mitigated with certain efforts. Such effects make it necessary for the clinician to use the drug only in situations where it will provide the greatest benefit with the fewest adverse effects. To the best of our knowledge, none of the reviews regarding ketamine have taken a comprehensive look at the drug’s uses in all territories of medicine. This review will serve to touch on its chemical data, pharmacokinetics and pharmacodynamics, medical uses, and adverse effects while focusing specifically on the drugs usage in anesthesia and analgesia.

Radvansky, B. M., Puri, S., Sifonios, A. N., Eloy, J. D., & Le, V. (2015). Ketamine-A Narrative Review of Its Uses in Medicine. American journal of therapeutics. https://dx.doi.org/10.1097/MJT.0000000000000257
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Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia

April 20, 2015 / Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , , ,

Abstract

BACKGROUND:

Schizophrenia has been associated with disturbances of thalamic functioning. In the light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether the modulation of the glutamatergic system via blockage of the NMDA-receptor might lead to changes of thalamic functional connectivity.

METHODS:

Based on the “ketamine-model” of psychosis we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55 minutes resting-state scan. 30 healthy volunteers were measured with pharmacological functional magnetic resonance imaging (fMRI) using a double-blind, randomized, placebo-controlled, crossover design.

RESULTS:

Functional connectivity analysis revealed significant ketamine-specific changes within the “thalamus hub network”, more precisely an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex.

CONCLUSIONS:

Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behaviour during the application of NMDA-receptor antagonists.

Höflich, A., Hahn, A., Küblböck, M., Kranz, G. S., Vanicek, T., Windischberger, C., … & Guertel, W. (2015). Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia. The international journal of neuropsychopharmacology. http://dx.doi.org/10.1093/ijnp/pyv040
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The hallucinogenic world of tryptamines: an updated review

April 16, 2015 / DMT, LSD, Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Psychology, Publications / By / , , , ,

Abstract

In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N,N-dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

Araújo, A. M., Carvalho, F., de Lourdes Bastos, M., de Pinho, P. G., & Carvalho, M. (2015). The hallucinogenic world of tryptamines: an updated review. Archives of toxicology, 1-23. https://dx.doi.org/10.1007/s00204-015-1513-x
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Mania following use of ibogaine: A case series

April 14, 2015 / Depressive Disorders, Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / 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
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Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

April 13, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, 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
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The use of ketamine as an antidepressant: a systematic review and meta-analysis

April 7, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, 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
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