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Psychiatry

Reviewing the ketamine model for schizophrenia

November 20, 2013 / Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / ,

Abstract

The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity,and abnormal cortical oscillations observed in acute schizophrenia.

Frohlich, J., & van Horn, J. D. (2014). Reviewing the ketamine model for schizophrenia. Journal of Psychopharmacology, 28(4), 287-302. http://dx.doi.org/10.1177/0269881113512909
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Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy

October 22, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify ‘classical’ monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.

Caddy, C., Giaroli, G., White, T. P., Sukhwinder, S. S. & Tracy, D. K. (2014). Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Advances in Psychopharmacology, 4(2), 75-79. http://dx.doi.org/10.1177/2045125313507739
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Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review

October 17, 2013 / Anxiety disorders / PTSD, MDMA, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , ,

Abstract

There is a good amount of evidence that exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD). Notwithstanding its efficacy, there is room for improvement, since a large proportion of patients does not benefit from treatment. Recently, an interesting new direction in the improvement of exposure therapy efficacy for PTSD emerged. Basic research found evidence of the pharmacological enhancement of the underlying learning and memory processes of exposure therapy. The current review aims to give an overview of clinical studies on pharmacological enhancement of exposure-based treatment for PTSD. The working mechanisms, efficacy studies in PTSD patients, and clinical utility of four different pharmacological enhancers will be discussed: d-cycloserine, MDMA, hydrocortisone, and propranolol.

de Kleine, R. A., Rothbaum, B. O., & van Minnen, A. (2013). Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review. European Journal of Psychotraumatoly, 17(4), 1-15. http://dx.doi.org/10.3402/ejpt.v4i0.21626
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Effective interventions in the problematic use of alcohol and other drugs

October 1, 2013 / LSD, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Substance Use Disorder / By / , , , ,

Abstract

OBJECTIVE:
Synthesize and assess the available scientific evidence from the period 2008-2012 on interventions of demonstrated efficacy in the treatment and rehabilitation of adolescents and adults engaged in the problematic use of alcohol and other substances.

METHODS:
A systematic review was undertaken with search and analysis of national and international literature on the subject in Spanish and English in the main international databases: PubMed/MEDLINE, LILACS, Embase, PsycINFO, SciELO, the databases of the York University Centre for Reviews and Dissemination (DARE, ETS Database), the Cochrane Library, and other sources of gray literature. The search criteria included randomized clinical trials and systematic reviews but excluded observational studies, qualitative studies, and articles of poor methodological quality.

RESULTS:
The final sample consisted of 69 studies. The psychosocial interventions shown to be effective were cognitive behavioral therapy, family interventions, self-help interventions using the Internet, couples behavioral therapy, community strengthening and family training, telephone monitoring and support, and integrated therapy for substance abuse disorder with anxiety and depression comorbidity. Pharmacological interventions of demonstrated effectiveness were acamprosate, lysergic acid diethylamide (LSD), and benzodiazepines in problematic alcohol use, as well as maintenance therapy with high-dose opioids.

CONCLUSIONS:
The demonstrated effectiveness of psychosocial and pharmacological interventions is slight but significant. However, strongly multidisciplinary interventions that use a cognitive behavioral approach and the involvement of people close to the consumer, as well as some of the specific pharmacological interventions, have been shown to yield the best results in terms of indicators of abstinence and prevention of relapses.

Lefio L. Á., Villarroel S.R., Rebolledo C., Zamorano P., & Rivas K. (2013). Effective interventions in the problematic use of alcohol and other drugs. Revista Panamericana de Salud Pública, 34(4), 257-266.
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Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial

October 1, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

OBJECTIVE:
Synthesize and assess the available scientific evidence from the period 2008-2012 on interventions of demonstrated efficacy in the treatment and rehabilitation of adolescents and adults engaged in the problematic use of alcohol and other substances.

METHODS:
A systematic review was undertaken with search and analysis of national and international literature on the subject in Spanish and English in the main international databases: PubMed/MEDLINE, LILACS, Embase, PsycINFO, SciELO, the databases of the York University Centre for Reviews and Dissemination (DARE, ETS Database), the Cochrane Library, and other sources of gray literature. The search criteria included randomized clinical trials and systematic reviews but excluded observational studies, qualitative studies, and articles of poor methodological quality.

RESULTS:
The final sample consisted of 69 studies. The psychosocial interventions shown to be effective were cognitive behavioral therapy, family interventions, self-help interventions using the Internet, couples behavioral therapy, community strengthening and family training, telephone monitoring and support, and integrated therapy for substance abuse disorder with anxiety and depression comorbidity. Pharmacological interventions of demonstrated effectiveness were acamprosate, lysergic acid diethylamide (LSD), and benzodiazepines in problematic alcohol use, as well as maintenance therapy with high-dose opioids.

CONCLUSIONS:
The demonstrated effectiveness of psychosocial and pharmacological interventions is slight but significant. However, strongly multidisciplinary interventions that use a cognitive behavioral approach and the involvement of people close to the consumer, as well as some of the specific pharmacological interventions, have been shown to yield the best results in terms of indicators of abstinence and prevention of relapses.

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., … Mathew, S. J. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 1134-1142. http://dx.doi.org/10.1176/appi.ajp.2013.13030392
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Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use?

October 1, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Editorial

Treatment-resistant depression is a significant clinical problem with great morbidity and mortality (1). The report by Murrough et al. (2), published concurrently with this editorial, of their two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression is an exciting and important step in evaluating a new and promising approach for these patients. Should our desire as clinicians to help these often desperate patients propel us to adopt ketamine now, or do we need to know more before proceeding? More studies, or change practice now? Let’s take a look.

The effect of ketamine on treatment-resistant depression appears to be both quick and quite substantial. Overall, two-thirds (64%) of the patients in the trial of Murrough et al. (2) responded, and about one-third (number needed to treat, or NNT, 2.8) responded specifically to ketamine, which is a large effect size. By way of comparison, the NNT in placebo-controlled phase 3 Food and Drug Administration registration trials is 6–7 in depressed outpatients who are not treatment resistant. About half of those in the Murrough et al. study who responded to ketamine relapsed over the next week—apparently without a sharp increase in suicidal ideation. Distressing adverse events were encountered on both the day of and the day following the infusion—including anxiety, which might raise the risk of suicidal thinking. Overall, eight of the 47 patients who received ketamine (17%) had significant dissociative symptoms, which could be quite disturbing to persons with borderline personality disorder. Blood pressure in the ketamine group rose from 122/72 mm Hg (pretreatment) to 141/81 (40 minutes after infusion), and two subjects required their infusions to be stopped for hemodynamic reasons. Other adverse effects were reported.

We do not know who responds to ketamine and who does not. An intriguing suggestion from Laje et al. (3), noted by Murrough et al. in their discussion, is that some of those patients who do not respond to ketamine are carriers of a Val66Met (rs6265) single-nucleotide polymorphism (SNP) that is associated with an attenuation of brain-derived neurotrophic factor (BDNF) functioning).

How certain and generalizable are the findings from this report? The internal validity of the study might be challenged since the subjective effects of midazolam are likely to be quite different than those of ketamine. If blinding was incomplete, the NNT might be larger. On the other hand, the overall study results were comparable at the two individual sites. Furthermore, as Murrough et al. note, additional studies of ketamine in treatment-resistant depression that provide similar response rates or effect sizes have been reported.

While certainty of the results is seemingly high, generalizability is much more limited since the inclusion and exclusion criteria were quite selective and properly so. Only 73 of the 116 screened participants entered the study. Those with acute suicidal risk, history of psychosis, unstable general medical conditions, substance abuse in the last 2 years, abnormal ECGs, or various other features were excluded.

In patients with nonresistant depression, we know that over three out of four who do receive antidepressant medication in practice are excluded from well-designed, internally valid randomized placebo-controlled phase 3 trials (4). The inclusion and exclusion criteria in the trial of Murrough et al. (2) were at least as, if not more, restrictive than those in the usual phase 3 trials. Perhaps only one in four patients with treatment-resistant depression in practice would have been eligible to enter this particular trial. Consequently, we do not know whether ketamine is safe or effective in a wider, more representative group of patients with treatment-resistant depression for whom ketamine is likely to be used. Potential risks in this wider group include exacerbation of prior or even concurrent psychiatric or general medical conditions—borderline personality disorder, posttraumatic stress disorder; bipolar spectrum disorders, substance abuse, cardiovascular problems, etc.

Additional practical issues loom. For example, all of the subjects in the trial of Murrough et al. were medication free for at least 7 days (28 days for fluoxetine) prior to the ketamine infusion. In practice, the acquisition of a 7-day medication-free state in patients with treatment-resistant depression is very challenging given the exigencies of practice and restrictive coverage policies. The effects of ketamine when used in patients who are taking other psychotropic agents represents an unexplored risk in ketamine treatment of patients with treatment-resistant depression.

In addition, how to manage those patients who both do and do not respond to ketamine is unknown but very important. Do the previously ineffective antidepressant medications now work in ketamine responders, so that the follow-on treatment is a return to these medications? Are repeated ketamine infusions called for in the nonresponders or responders? Do they work?

While we lack several key pieces of information that are needed before we revise practice, this study does take several important steps: 1) it provides strong clinical evidence that the pathways targeted by ketamine deserve greater investigation and should be targets for drug development; 2) it suggests that some SNPs may usefully exclude at least some patients with treatment-resistant depression from ketamine infusion, which is an important step in targeting treatment (5); and 3) it suggests that with informed consent, a wider range of patients with treatment-resistant depression should be studied under controlled circumstances to better identify those who should and should not get ketamine—whether because of lack of efficacy or because of side effects. Multisite registries using an open design or point-of-care randomized trial designs (6) could be a rapid way to move the field forward at lower costs to elaborate on the risks as well as the pretreatment predictors of ketamine treatment.

While insufficient to recommend a wholesale change in practice presently, these results certainly provide substantial hope for patients with treatment-resistant depression, insight into the biology of this condition, and a major obligation by clinician scientists and funding agencies to answer this next set of important clinical questions for our patients with refractory depression.

Rush, A. J. (2013) Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use? American Journal of Psychiatry, 170(10), 1079-1081. http://dx.doi.org/10.1176/appi.focus.12.2.244
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Self-Medication of LSD and MDMA to Treat Mental Disorders: A Case Series

September 18, 2013 / Anxiety disorders / PTSD, Depression, LSD, MDMA, Other subjects, Papers, Psychiatry, Psychology, Publications / By /

Abstract

50 years ago LSD was prescribed to treat a variety of mental illnesses. More recently LSD and MDMA (ecstasy) have become widely used outside medicine as both recreational drugs and by some patients as ‘self-medication’. These brief reports gather together five patients’ experiences using psychedelic drugs to treat their mental disorders. They are discussed in relation to the medical profession’s current growing interest in re-visiting psychedelic drugs as therapeutic treatments in psychiatry. The first case describes the successful self-treatment for depression using LSD, followed by a case in which doctors administered LSD in the 1960s and 1970s to successfully treat a case of obsessive-compulsive disorder (OCD) and chronic fatigue syndrome. The third and fourth cases describe the successful self-treatment of OCD using respectively MDMA and then LSD and the final case describes a self-treatment with LSD to manage Anorexia Nervosa. All the participants describing their use of these drugs give a positive report of self-treatment with minimal adverse effects. They also all support a resumption of more research into the therapeutic use of hallucinogens/psychedelic drugs as potential clinical therapies.

Sessa, B. (2010). Self-medication of LSD and MDMA to treat mental disorders: A case series. The Journal of Alternative Medicine Research, 2(2), 245-249.
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A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment

September 1, 2013 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Substance Use Disorder / By / ,

Abstract

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states.

Burdick, B. V., & Adinoff, B. (2013). A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment. The American Journal of Drug and Alcohol Abuse, 39(5), 291-297. http://dx.doi.org/10.3109/00952990.2013.811513
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Psychedelics and Mental Health: A Population Study

August 19, 2013 / Cacti / Mescaline, MDMA, Mushrooms / Psilocybin, Other subjects, Papers, Psychiatry, Psychology, Publications, Safety / By / ,

Abstract

Background
The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline.

Objective
To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population.

Method
Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events.

Results
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.

Conclusion
We did not find use of psychedelics to be an independent risk factor for mental health problems.

Krebs, T. S., & Johansen, P. Ø. (2013) Psychedelics and Mental Health: A Population Study. PLoS ONE, 8(8), 1-9. http://dx.doi.org/10.1371/journal.pone.0063972
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Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression

June 25, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

OBJECTIVES:
Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.
METHODS:
In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.
RESULTS:
Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.
CONCLUSION:
The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.
Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., & Palenicek, T. (2013). Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinology Letters, 34(4), 287-293.
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