Guest Commentary by W. Vaughn McCall, MD
- Gabapentin Treatment for Alcohol Dependence: A Randomized Clinical Trial
- The Natural History of Insomnia: Acute Insomnia and First-Onset Depression
- Rapid Antidepressant Effects of Repeated Doses of Ketamine Compared With Electroconvulsive Therapy in Hospitalized Patients with Major Depressive Disorder
- Electroconvulsive Therapy-induced Brain Plasticity Determines Therapeutic Outcome in Mood Disorders
- Addressing Risks to Advance Mental Health Research
Mason BJ, Quello S, Goodell V, et al. JAMA Intern Med. 2014;174(1):70-77.
To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.
Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.
Insomnia is a common symptom during abstinence in alcohol dependence, occurring in up to 50% of patients, and lasting for weeks or months into the period of abstinence. Further, the presence of insomnia during abstinence is a major risk factor for alcoholic relapse. Not surprisingly, clinicians are reluctant to use controlled substances such as hypnotics to address insomnia during abstinence. The present study is a larger replication/confirmation of prior work showing that moderate-dosed gabapentin improves sleep, reduces craving for alcohol, and extends the period of sobriety. This study adds to the accumulating evidence that gabapentin should be an early consideration in addressing insomnia among those with alcohol dependence.
Ellis JG, Perlis ML, Bastien CH, et al. Sleep. 2014;37(1):97-106.
While many studies have examined the association between insomnia and depression, no studies have evaluated these associations within a narrow time frame, with specific reference to acute and chronic insomnia, and using polysomnography. In the present study, the association between insomnia and first-onset depression was evaluated taking into account these considerations.
The transition from acute to chronic insomnia is presaged by baseline differences in sleep architecture that have, in the past, been ascribed to major depression, either as heritable traits or as acquired traits from prior episodes of depression. The present findings suggest that the “sleep architecture stigmata” of depression may actually develop over the course transitioning from acute to chronic insomnia.
Research in the relationship between sleep and depression has revealed two strong findings, one of them a laboratory finding, the other a clinical finding. Forty years ago we received the first reports that a short latency to REM sleep was more commonly seen in depression than in normals. Over the last 20 years has come the discovery that insomnia is a risk factor for new-onset depression in persons who were never before mentally ill. These two relationships converge in this report by Ellis et al., who now report that persons with acute insomnia are more likely to progress to chronic insomnia if they have a short REM latency, and secondly that of those who do transition to chronic insomnia, a short REM latency is predictive of incident depression. The importance of this paper is the discovery that the polysomnographic marker of depression (short REM latency) actually precedes the onset of depressive illness.
Ghasemi M, Kazemi MH, Yoosefi A, et al. Psychiatry Res. 2013 Dec 13. pii: S0165-1781(13)00771-3. doi: 10.1016/j.psychres.2013.12.008.
Accumulating evidence suggests that N-methyl-d-aspartate receptor (NMDAR) antagonists (e.g. ketamine) may exert rapid antidepressant effects in MDD patients. In the present study, we evaluated the rapid antidepressant effects of ketamine compared with the electroconvulsive therapy (ECT) in hospitalized patients with MDD.
This study showed that ketamine is as effective as ECT in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with the ECT.
This study builds upon previous work showing that slow infusion of ketamine over 45 minutes is an effective antidepressant. However, the provocative aspect of this paper is the notion that, compared with ECT, ketamine has a superior antidepressant effect over one week of treatment with ketamine versus ECT, and that ketamine keeps the upper hand for the week which follows one week of treatment. This work is exciting, but there are several reasons to not over-interpret the meaning of the data. First, the study was small (N=9 per group), and hence warrants replication with a larger group. Second, one week of ECT treatment would never be construed as a full course of ECT. So, while ketamine may perhaps work faster over the first week, it is still possible, perhaps even likely, that ECT has a more complete or durable antidepressant result as compared with ketamine. Indeed, some experts have postulated that antidepressants with the fastest treatment effect ( think about sleep deprivation) also have the fastest decay of therapeutic action.
Dukart J, Regen F, Kherif F, et al. Proc Natl Acad Sci U S A. 2013 Dec 30.
There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders. This stems from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to as a "barbaric" form of placebo effect.
Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.
This fascinating paper on the topic of right unilateral (RUL) ECT-related changes in MRI-determined brain gray matter volumes (GMV) is encumbered by a relatively small sample size (5 bipolar patients and 5 unipolar depressives) and a complicated statistical analytic approach. Still, the results intriguingly show that RUL ECT is associated with regional changes in GMV only in the right hemisphere, and these manifest as increased GMV in the hippocampal complex, and decreases in GMV in the middle and inferior frontal cortex. The importance of these findings is that it further elaborates the idea that ECT promotes neuroplasticity with a regionally-differentiated effect. Whether the strict localization of the neuroplasticity findings to the right hemisphere is a function of RUL ECT is unknown, and in the future it would be interesting to contrast the investigative method in patients allocated to RUL versus bilateral ECT.
Iltis AS, Misra S, Dunn LB, et al. JAMA Psychiatry. 2013;70(12):1363-1371. doi: 10.1001/jamapsychiatry.2013.2105.
Communication and management are essential to the ethical conduct of research, yet addressing risks may be time consuming for investigators and institutional review boards may reject study designs that seem too risky. This can discourage needed research, particularly in higher-risk protocols or those enrolling potentially vulnerable individuals, such as those with some level of suicidality. Improved mechanisms for addressing research risks may facilitate much needed psychiatric research. We endeavor to provide mental health researchers with practical approaches to (1) identify and define various intrinsic research risks, (2) communicate these risks to others (eg, potential participants, regulatory bodies, and society), (3) manage these risks during the course of a study, and (4) justify the risks.
Empirical data on risk communication, managing risks, and the benefits of research can support the ethical conduct of mental health research and may help investigators better conceptualize and confront risks and to gain institutional review board-approval.
Both pharmaceutical companies and institutional review boards (IRBs) are risk adverse…. No one wants a serious adverse event, a death, a complaint, or litigation “on their watch.” As a result, only a small proportion of clinical trials in psychiatry include patients with active suicidality, catatonia (or other forms if incapacity), or life-threatening medical illness. While the NIH and medical foundations may be somewhat more willing to support high-risk projects, IRBs are still reluctant to approve such projects. This tendency inadvertently leads to an injustice such that very little science is available to guide the clinical care of our most vulnerable populations. It is reminiscent of our past in which clinical trials and other medical science ignored women and minorities, leading to the NIH insistence of inclusiveness. In this paper, Iltis et al. describe a series of processes that investigators and IRBs can use to include psychiatric populations of great interest who have been previously excluded.