TMS Treatment for Depression & Toxoplasma

Research Updates in PsychiatryStudy Looks at Use of TMS to Treat Depression

Transcranial magnetic stimulation, or TMS, was approved by the FDA for treatment of major depression in October 2008. A newly published observational study evaluating the effectiveness of TMS treatment in more than 300 patients at 42 clinical settings across the United States has found that most patients responded well to this intervention, with few adverse effects (Carpenter LL et al, Dep Anx 2012;29(8):587–596).

The study followed 307 outpatients who were approved for TMS treatment due to failing at least one antidepressant trial (multiple failures were not required). Most treatment settings (76%) were private clinical practices, and TMS was paid for either by patients themselves or by their insurance provider. Importantly, both subjects and investigators received a “modest remuneration” for their participation in the study. Also, there was no control or “sham TMS” group.

The primary outcome measure was the Clinical Global Impressions-Severity of Illness (CGI-S) scale. This scale simply asks the question “how mentally ill is the patient at this time,” measured by the clinician on a scale of 0 to 7. In the study, mean CGI-S scores decreased from 5.1 at the start of treatment to 3.2 at the end of treatment (ie, the point at which the clinician felt “maximum improvement” was reached). Response rate was 58.0% while remission rate was 37.1%. Similar results were found on two secondary outcome measures, the patient self-rating scales PHQ-9 and IDS.

Given the generally positive results, investigators searched for patient-specific factors that might predict a beneficial response to TMS. They found that patients younger than 55 years of age and who had less severe depression were more likely to benefit from treatment than others. Furthermore, those who had failed only one antidepressant (54% of the sample) did better than those who had failed two or more.

TCPR’s Take: At first glance, this naturalistic study seems to show an impressive benefit of TMS in real-world settings. Side effects were minimal (there was one seizure, in a woman taking several concurrent medications who was “sleep-deprived” at the time of TMS) even with an average of 28.3 TMS sessions over 42 days. However, the take-home message is called into question by the absence of a control group, the financial incentive to both patients and providers, and the sponsorship of the paper by the TMS device manufacturer. Most important, given the increasing emphasis on placebo response and patient expectations, it would have been interesting to determine whether patients’ (or providers’) beliefs about TMS influenced response to treatment, but this was not assessed.


Parasite Infection Possible Precursor to Suicidal Behavior

A major thrust of much psychiatric research is to identify predictors of suicidality, in hopes of intervening earlier to prevent this devastating outcome. In a recent study, a Danish group made a surprising contribution to this endeavor by identifying Toxoplasma gondii infection as a possible precursor to suicidal behavior.

Toxoplasma is a parasite commonly found in the GI tract of cats, and is carried by almost one-third of adult humans. Humans become infected by exposure to cat feces, eating undercooked meat, and eating unwashed vegetables. Some have linked acute infection to psychotic symptoms, and Toxoplasma antibodies have been found to be elevated in patients with schizophrenia.

Between 1992 and 1995, more than 45,000 pregnant women living in five counties in Denmark, and their newborns, were screened for Toxoplasma IgG antibodies. Nearly 27% of the women were seropositive for IgG, reflecting past infection. Among these women, there were a total of 488 incidents of self-directed violence in the next 10 years of follow-up. These were more common in seropositive women, with a relative risk (RR) of 1.53. The risk was elevated with higher IgG levels, up to a relative risk of 1.91 in those with the highest concentration of antibodies. Also, the risk was greater in women with no past history of mental illness (RR=1.56).

More than 500 women had a prior history of self-directed violence, and 84 had recurrent acts during the study period. Here, too, seropositive women were at higher risk (RR=1.54), although this was not significant. Finally, there were 18 completed suicides in the entire study population, and seropositive women were also overrepresented in this group (n=8), with a relative risk of 2.05. Even though this risk was not significantly elevated, the very low numbers of completed suicides make it hard to draw conclusions about this group.

TCPR’s Take: These results offer an interesting—if unexpected—insight into the neurobiology of self-directed violence. While it’s still a stretch to conclude that Toxoplasma infection causes suicidality, the authors argue that elevations in inflammatory compounds such as interleukin-6 or tumor necrosis factor-a, or in downstream mediators like kynurenines (from the breakdown of tryptophan in the Toxoplasma parasite) might influence behavior. The study’s findings are limited by the low incidence of actual suicide or self-harm, the inability to assess acuity of Toxoplasma infection, and the exclusion of men. Nevertheless, these findings open the way for further research into biological correlates or biomarkers of violence and suicidality.


Study Suggests DCS Not Effective in PTSD Treatment

Exposure therapy is a cognitive behavioral strategy that serves as a core treatment for anxiety disorders. Animal and human studies alike have supported the use of D-cycloserine (DCS) as an agent to augment the effectiveness of exposure therapy in specific phobia, social phobia, panic disorder, and obsessive-compulsive disorder. D-cycloserine, also known as Seromycin, is an antituberculosis drug that also acts as a partial agonist of the NMDA receptor. It is hypothesized that stimulation of NMDA receptors helps enable “extinction learning,” or the remodeling of pathways in the amygdala to decrease conditioned fear responses.

A new study, however, finds that DCS does not improve treatment responses in patients undergoing prolonged exposure therapy for post-traumatic stress disorder, or PTSD. Sixty-seven patients with PTSD underwent a standardized program of up to 10 sessions of prolonged exposure therapy. Half (33) received 50 mg of D-cycloserine one hour before each exposure session while the others received placebo. Most of the patients completing the trial reported a decrease in symptoms as measured by the Post traumatic Stress Symptom Scale (PSSSR). Patients taking DCS had higher response rates (odds ratio for response was 2.83, 95%CI=1.05–7.61), but statistical tests showed that this could not be attributed to DCS, probably because of differences in baseline severity between groups.

Patients were allowed to continue their other medications during the study, and the events underlying each patient’s PTSD varied from sexual assault to traffic accidents. Also, nearly one-third of the patients dropped out of the study. These factors might explain the lack of an obvious benefit of DCS. A subgroup analysis, however, showed that those patients who required the full 10 sessions of therapy were significantly more likely to benefit from DCS: mean PSS-SR scores decreased by 43.9% in those receiving DCS, vs only 7.8% in those receiving placebo (de Kleine RA et al, Biol Psychiatry 2012;71:962–968).

TCPR’s Take: DCS does not appear to enhance treatment response in patients undergoing exposure therapy for PTSD. There was some suggestion that it may help patients with serious symptoms who require longer treatment, compared with those who complete treatment earlier. But previous, smaller studies on DCS in exposure therapy for other anxiety disorders showed effects in just a few sessions, and another recent paper shows that patients undergoing short-term exposure for war-related PTSD actually did worse with DCS (Litz BT et al, J Psychiatr Res 2012:online ahead of print). Whether DCS has a place in treating PTSD is still not clear, but these studies suggest that it probably contributes little to a good, evidence-based modality like exposure therapy.

TMS Treatment for Depression & Toxoplasma

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The Carlat Psychiatry Report
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This article was published in print 9/2012 in Volume:Issue 10:9.