Monday, May 9, 2011

Opioids for Treatment Resistant Depression?

My colleague, Mark Rose, recently submitted this post about the potential use of buprenorphine as an antidepressant treatment for treatment resistant depression. To our knowledge, no further studies of this have been done. Perhaps it's time?


Buprenorphine may be effective in treatment-refractory depression

Mark E. Rose, MA
Licensed Psychologist

Persons with major depressive disorder (MDD) are considered treatment-refractory (TRD) when they fail to respond to multiple trials of antidepressant medication from different classes (Keller 2005). TRD is a devastating condition that results in substantial health care and economic cost, and untold suffering to the patient and family members (Nierenberg et al. 2007). Most FDA-approved antidepressant drugs act through monoamine reuptake inhibition, and medications that act through alternate mechanisms need to be available to patients with unrelenting depression that is untreatable with conventional antidepressants. The results of a study published 15 years ago hint that a currently available drug may provide greater benefit to patients with TRD than any other known pharmaceutical agent.

Although opioids were used to treat MDD until the late 1950s, research evaluating their antidepressant potential has been very rare in the past 60 years (Berrocoso et al. 2009). The synthetic opioid buprenorphine is a partial mu receptor agonist and kappa receptor antagonist, is exceptionally safe in overdose, and produces substantially less euphoria than pure mu receptor agonists such as morphine and oxycodone. A small study (Bodkin et al. 1995) evaluated the therapeutic potential of buprenorphine in the treatment of TRD. The 10 study participants averaged a 20.7–year duration of unipolar major depression, 7.6 previous unsuccessful antidepressant trials, and a HAM-D score of 28.1. Buprenorphine was initiated in open-label manner at 0.15 mg/d with maximum upward titration to 1.80 mg/d over the 4-6 week trial (final mean dose 1.26 mg/d). Three subjects dropped out due to malaise, nausea, and dysphoria. Of the remaining 7 subjects, 6 achieved marked clinical improvement. The mean endpoint HAM-D score was 10.7, a 60.7% reduction from baseline, and 4 patients achieved complete remission (HAM-D ≤ 6). The mean overall level of functioning increased 45.5% and mean subjective depression rating decreased 50%. Significant improvement became apparent at the end of week 1.

The authors conclude that the results are remarkable, with the number of previous treatment failures, the level of disease severity, and the duration of improvement arguing against placebo effect as the basis of treatment response. Patients did not report euphoria or intoxication but instead felt ‘more normal’, which together with the 33% drop-out suggest limited abuse liability in persons with TRD. These results are literally begging for replication, but sadly, despite awareness of this data for 15 years, researchers have not conducted follow-up studies due to the stigma surrounding opioid drugs and their association with addiction.

Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry. 2005;66(Suppl 8):5-12.

Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic
management of treatment-resistant depression. Psychiatr Clin North Am. 2007;30(1):13-29.

Berrocoso E, et al. Opiates as antidepressants. Current Pharmaceutical Design. 2009;15:1612-1622.

Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:49-57.

Thursday, May 5, 2011

Research Study Results: Skepticism Required!

This new study identified some functional neuroimaging correlates to performance on a task that measures something called "delay discounting." This now highly popular test (among scientists) gives people a choice or series of choices that boils down to this question: "Do you want a smaller reward (typically money) sooner, or a larger reward later?" For example, a subject might be asked to decide between getting $1 right now, or getting $20 in two weeks. "Delay discounting" refers to discounting the value of a future reward, thus increasing the likelihood of choosing the smaller reward sooner. While there have been many such studies, I'm posting this one because of the comments made by Dan Hommer at the National Institute on Alcohol Abuse and Alcoholism. His comments focus on the concept of "impulsivity." As it turns out, there is no gold standard for measuring this construct, nor is there any consensus about what it means in more than general terms. The same holds true for many other terms used in imaging and other studies, including reward, behavioral inhibition and disinhibition, liking, wanting, attention and so forth. Bottom line: read or listen to the results of studies like this skeptically. Remember that scientists and media professionals want something to be newsworthy, leading to inflation of the importance and clarity of much research.


Researchers Link Alcohol-Dependence Impulsivity to Brain Anomalies


May 1, 2011

Researchers already know that alcohol dependence (AD) is strongly associated with impaired impulse control or, more precisely, the inability to choose large, delayed rewards rather than smaller but more immediate rewards. Findings from a study using functional magnetic resonance imaging (fMRI) to investigate the neural basis of impulsive choice among individuals with alcohol use disorders (AUDs) suggest that impulsive choice in AD may be the result of functional anomalies in widely distributed but interconnected brain regions that are involved in cognitive and emotional control.

Results will be published in the July 2011 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"Individuals with AD score higher on questionnaires that measure impulsivity -- for example, 'I act without thinking' -- are less able to delay gratification, and are less able to inhibit responses," said Eric D. Claus, a research scientist with The Mind Research Network and first author of the study.

Given that impulsive choice in AUDs has been associated with impairment of frontal cortical systems involved in behavioral control, Claus explained, this study was designed to examine the neural correlates of one specific aspect of impulsivity, the ability to delay immediate gratification and instead choose rewards in the future.

"We investigated this choice process in individuals with alcohol use problems ranging from alcohol abuse to severe AD that required treatment," said Claus. "This is the largest study to date that has investigated the neural correlates of impulsive choice in AD, which enabled us to examine the full range of AUDs instead of only examining extreme group differences."

Claus and his colleagues examined 150 individuals (103 males, 47 females) with various degrees of alcohol use. All of the participants completed a delay discounting task -- during which two options were presented, a small monetary (e.g., $10) reward available immediately or a larger monetary reward (e.g., $30) available in time (e.g., two weeks) -- while undergoing fMRI. Impulsive choice was defined as the selection of the more immediate option.

"We showed two things," said Claus. "We replicated previous research by showing that AUD severity was associated with a greater tendency to discount future rewards. In addition, we showed that when individuals with more severe AUDs did delay gratification, they engaged the insula and supplementary motor area -- regions involved in emotional processing and response conflict -- to a greater degree than individuals with less severe AUDs. In summary, these findings suggest that the dysfunction in these regions is graded and increases as a function of AUD severity, rather than operating as an all-or-none function."

"This work showed that the brains of alcoholics don't behave all that differently from the brains of non-alcoholics during delay discounting but that the alcoholic brain had to work harder when they chose the delayed reward," said Daniel W. Hommer, chief of the Section of Brain Electrophysiology & Imaging at the National Institute on Alcohol Abuse and Alcoholism. "Many different studies have shown similar results, that is, alcoholics have a greater increase in brain blood flow to perform the same task as non-alcoholics."

"The current study suggests that the neural dysfunction underlying impulsive choice seems to increase with AD severity," added Claus. "Now that we know that this neural dysfunction is associated with impulsivity, the next steps are to determine whether this impulsivity predates the onset of AD and whether neural measures of impulsivity can predict who will respond best to particular types of treatment. Further, the particular neural dysfunction that we observed indicates that individuals with more AD may be more impulsive because their brain is aversive to delay gratification, and not because it is rewarding to be impulsive. Clinicians might need to deal directly with the aversion of choosing future benefits over immediate ones."

"The most important thing about this paper is that it leads you to question what people mean by impulsive behavior and how should it be measured," said Hommer. "The field has defined increased discounting of time -- failure to delay gratification -- as a good measure of impulsiveness, but the results reported in this paper say 'Wait a minute, delay discounting does not correspond to what is usually meant by impulsiveness.' Rather, brain activity during a delay discounting task looks more like how the brain responds during conflicted decision-making than it does during rapid, unconflicted choice of a highly valued goal." Hommer added that this sort of debate is important to researchers, forcing them to think more carefully about what they mean by impulsive choice.

Monday, May 2, 2011

Evidence Stronger for Cannabis-Psychosis Link

I've been a skeptic about the potential role of cannabis as an independent risk factor for developing psychosis, but this new study addresses some of the weaknesses of previous studies and shows a strong association between persistent cannabis use and the later development of psychosis. They only studied cannabis use that started after the study baseline to eliminate the effects of preexisting use, and they excluded anyone at baseline with any psychotic symptoms. The authors suggest that the risk might involve increasing the persistence of subclinical psychotic phenomena that would otherwise be transient, an interesting hypothesis. Underlying that suggestion is recent evidence that psychotic phenomena exist along a continuum from minor transient symptoms (quite common) to persistent and then more severe symptoms. Also note that the risk associated with cannabis was independent of family history of psychosis. There are still many unanswered questions about this link, but the evidence for it is growing and is strong enough now that warning parents and adolescents is probably warranted. Here's the link to the article.


BMJ 2011; 342:d738

Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study
Rebecca Kuepper, research psychologist1, Jim van Os, professor1, visiting professor2, Roselind Lieb, professor34, Hans-Ulrich Wittchen, professor45, Michael Höfler, research statistician5, Cécile Henquet, lecturer1
+ Author Affiliations

1Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University Medical Center, Maastricht, Netherlands
2King’s College London, King’s Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, UK
3Department of Psychology, Division of Epidemiology and Health Psychology, University of Basel, Switzerland
4Max Planck Institute of Psychiatry, Munich, Germany
5Institute of Clinical Psychology and Psychotherapy, Technical University Dresden, Germany
Correspondence to: J van Os, Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University Medical Center, PO Box 616, NL-6200 MD, Maastricht, Netherlands
Accepted 31 December 2010
Objective To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis).

Design Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study).

Setting Population based cohort study in Germany.

Participants 1923 individuals from the general population, aged 14-24 at baseline.

Main outcome measure Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI).

Results In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively.

Conclusion Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms