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Direct electrical alteration of brain circuitry—neuromodulation—is the oldest somatic treatment still used in psychiatry since the arrival of ECT in 1938. This chapter reviews the expansive literature on neuromodulatory strategies that are either clinically available (ECT, rTMS, VNS) or under investigation (TNS, tDCS, DBS) for the treatment of psychiatric disorders refractory to standard (psychotherapy or pharmacotherapy) treatments. Rather than attempt a full review of each modality, this chapter will focus on the current (September 2017) state of knowledge on how each modality may contribute to relieving the tremendous suffering of individuals afflicted with refractory psychiatric conditions and what the future may hold. In particular, this section will address treatment-refractory addiction, anxiety disorders, bipolar disorder, depression, OCD, PTSD, and schizophrenia but, because of space limitations, will exclude cognitive, eating, or developmental disorders even though neuromodulation has been tried experimentally for these other conditions.

The anti-suicidal benefit of lithium on suicidal behavior in bipolar disorder is well-established. Data are mixed on the effects of divalproex and carbamazepine.Retrospective chart review study of 405 veterans with bipolar disorder followed for a mean of 3 years, with month by month review of clinical progress notes, and systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Comparison of suicide event rates (events/100 patient years) between mood stabilizers and during-vs-after discontinuation of mood stabilizers, with linear regression analysis for influence of potential confounding variables, and robust bootstrap confirmation analysis.No completed suicides occurred during or after discontinuation of monotherapy. Rates of non-lethal suicidal behavior were similar during lithium (2.49), divalproex (4.67) and carbamazepine (3.80) monotherapies. There was a sixteen fold greater, highly statistically significant non-lethal suicidal event rate after discontinuation compared with during mood stabilizer monotherapy (55.89 vs. 3.48 events/100 patient years; Chi2=13.95; df=1; p0.0002). On compared with off treatment differences were similar for the three different agents.Treatments were uncontrolled in this naturalistic setting, and data were analyzed retrospectively.Lithium and the anticonvulsants may show similar benefits in protecting bipolar patients from non-lethal suicidal behavior when careful analysis of clinical data is done to confirm medication adherence/non-adherence. Findings in this study were similar to those of a previous study that applied the same methodology in a private practice setting.

Antidepressant-induced mania and cycle acceleration is a potential risk in bipolar patients. Another serious risk of antidepressants, that of increasing suicidal behavior, has been identified in some affectively ill populations. However, there is a dearth of knowledge about the effects of antidepressants on suicidal behavior specifically in bipolar patients. Methods Retrospective chart review of 405 veterans with bipolar disorder followed for a mean of three years, with month by month systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Chi-squared comparison of (log) rates of suicidal events during mood stabilizer monotherapy, antidepressant monotherapy, and combination of mood stabilizer and antidepressant. Results Suicidal behavior event rates (per 100 patient years) were greatest during treatment with antidepressant monotherapy (25.92), least during mood stabilizer monotherapy (3.48), and intermediate during mood stabilizer + antidepressant combination treatment (9.75). These differences were statistically significant. Limitations In a clinical setting, antidepressants may have been prescribed because patients were deemed at greater risk of suicidality. Conclusions During treatment with antidepressants (even when coupled with mood stabilizers), patients with bipolar disorder have significantly higher rates of non-lethal suicidal behavior compared to those on mood stabilizers without antidepressants, and thus require careful monitoring.

Post-traumatic stress disorder (PTSD) is a serious psychiatric consequence of trauma that occurs in a proportion of individuals exposed to life-threatening events. Trauma-focused psychotherapy is often recommended as first choice for those who do not recover spontaneously. But many individuals require medications. In the US, only paroxetine (PRX) and sertraline (SRT) are FDA approved for PTSD. But response and remission rates with these medications are low, so numerous other pharmacologic interventions have been tried. To date, there has not been a systematic review of the data on what are the best next-step pharmacologic strategies for individuals who fail standard treatments. To that end, we review 168 published trials of medications other than PRX or SRT and provide a detailed analysis of the 88/168 studies that describe alternative pharmacologic interventions in patients refractory to other treatment. We also review clinical factors relevant to treatment-refractory PTSD; the neurobiology of extinction, as well as evidence-based psychotherapy and neuromodulation strategies for this condition.

Background Non-suppression on the dexamethasone suppression test (DST) in unipolar depression has been found to be associated with completed suicide, with less consistent data for attempted suicide and hospitalizations for suicidality. The purpose of this study was to examine DST non-suppression as a predictor of these three aspects of suicidal behavior. Methods Records were reviewed for 101 patients who met criteria for major depressive disorder and/or dysthymic disorder and had a DST performed. All patients were treated naturalistically and were followed for an average of 2 years. DST suppressors and non-suppressors were compared with respect to three outcomes: (1) completed suicide; (2) attempted suicide; and (3) hospitalizations for suicidality. Results DST non-suppressors were significantly more likely to have completed suicide or be hospitalized for suicidality than DST suppressors, with a non-significant trend for attempts. Total suicidal events were also significantly more frequent in the non-suppressor group. Limitations Axis II diagnoses and severity of illness were not assessed. Knowledge of DST results may have influenced the decision to hospitalize patients. Conclusions DST non-suppression identifies unipolar depressed patients with a higher risk for future suicide completion or hospitalization for suicidality. Performance of DST upon initiation of treatment may be a useful adjunct in identifying suicidal risk.

Objective: To compare the rates of suicidal behaviour during vs. after discontinuation of treatment with antidepressants, and to determine the comparative rates of suicidal behaviour for patients maintained on tricyclic (TCA) vs. selective serotonin reuptake inhibitor (SSRI) antidepressants. Method: Charts were reviewed for 521 patients with major depressive disorder and/or dysthymic disorder. Periods of active treatment or discontinuation with SSRIs or TCAs were determined. Rates of completed suicide, suicide attempts, and hospitalization for suicidality were analyzed. Results: There was greater than a five-fold increase in risk for suicidal behaviour after discontinuation of antidepressant treatment (P

Background: Lithium has been found to be effective in reducing suicide rates during long term treatment of patients with bipolar disorders. Data on the efficacy of anticonvulsant mood stabilizers in reducing suicide risk are sparse. Method: Charts of 140 bipolar patients treated continuously for a minimum of 6 months during a 23-year period of private practice by the senior author were extracted from nearly 4000 patient records. Data extracted from the charts were incidence of completed suicide, number of suicide attempts, and number of hospitalizations for suicidal ideation or behavior per 100 patient-years of either ‘on’ or ‘off’ lithium or anticonvulsant mood stabilizer monotherapy. Results: Only one completed suicide (during a period off of lithium) occurred in the patients studied. Incidence of non-lethal suicidal behavior was not different during treatment with lithium, compared with anticonvulsants. Being on a mood stabilizer significantly protected against suicidal behavior. The relative protective effect was more modest than in reports from other treatment settings. Limitations: This was a retrospective chart review study of naturalistically treated patients. Conclusions: Treatment of patients with bipolar disorder with either lithium or anticonvulsant mood stabilizers was associated with reduced risk of suicidal behavior. This study did not find evidence for a difference in the protective effect of the two types of mood stabilizing medications against non-lethal suicidal behavior in the naturalistic setting of private practice.

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. (Am J Addict 2015;24:203–205)

Background: Previous research has identified a high rate of anxiety disorders comorbidity in patients with a primary mood disorder diagnosis. Discrepancies between studies in the comorbidity prevalence of specific anxiety disorders in mood disorders, and of anxiety disorders comorbidity between unipolar depression and bipolar mood disorder are in part due to differences in sampling and diagnostic assessment methodology. Method: The authors reviewed the charts of 138 patients who received the SCID-P for DSM-III on enrollment in a Mood Disorders Clinic during the period 1982 through 1988. The comorbidity of specific DSM-III Anxiety Disorders with specific mood disorders was determined and comparatively examined using non-parametric statistics. Results: There was high overall comorbidity of anxiety disorders that did not differ between bipolar and unipolar subjects. There were no differences in the comorbidity of individual anxiety disorder diagnoses in the unipolar vs. bipolar groups. However, in unipolar patients with, compared to those without an additional diagnosis of dysthymia, there was greater overall anxiety disorders comorbidity, with a particularly high prevalence of generalized anxiety disorder. Limitations: The subgroup of patients with bipolar I disorder was relatively small (N=8). Conclusion: Mood and anxiety disorders comorbidity is complex and presents a continuing challenge for both clinicians and researchers.

Objective Antipsychotics are commonly used in bipolar disorder, with newer (SGA) agents increasingly replacing FGA antipsychotics, particularly in bipolar depression. There are few data on differences between FGA and SGA antipsychotics in terms of their relationship to suicidal behavior in bipolar disorder. Method This was a retrospective chart review of 161 bipolar veterans treated naturalistically with antipsychotics at a university-affiliated VA hospital and clinics for up to 8 years. Charts were reviewed to determine monthly antipsychotic use and occurrence of suicidal behavior: completed suicide, attempted suicide or hospitalization to prevent suicide. Suicidal behavior events were compared across patients during treatment with individual antipsychotics and FGAs or SGAs as a class. Results Non-lethal suicide events were more common during FGA than SGA monotherapy (9 events/110 months of exposure vs. 6 events/381 months of exposure; χ2=9.65, p=0.002). Suicide event rates did not differ between FGAs and SGAs when used in conjunction with mood stabilizers. Event rates were lower with lithium than anticonvulsants when used in conjunction with antipsychotics. No differences were found between olanzapine, risperidone and quetiapine. Limitations The retrospective chart review methodology may have led to confounding by indication and diagnostic inaccuracy. No completed suicides occurred. Study participants were primarily male veterans. Results may not be generalizable to SGAs marketed since 2003. Conclusions FGA antipsychotic monotherapy may be associated with higher suicidal behavior risk than SGA antipsychotic monotherapy. Antipsychotics used in conjunction with mood stabilizers, particularly lithium, are associated with lower rates, independent of antipsychotic subtype.

Seventeen patients who met DSM-III-R criteria for social phobia were seen in an eight week open trial of buspirone. Eleven subjects completed the study, having taken an average of 48 mg per day of medication by the end of week 8. Rating scales of generalized anxiety, social anxiety, depression, and disability were administered. Preliminary findings indicated that 1) buspirone is an effective anxiolytic for anxiety in general, and 2) generalized social phobia symptoms partially responded to buspirone, although few patients responded dramatically. The limitations of this study and some problems with the assessment instruments are discussed. Recommendations for future studies are offered.

The controlled trial is now the standard for assessing efficacy of new treatments in Psychiatry, as it is in the rest of medicine. Psychiatric outcomes with treatment are influenced by concurrent psychosocial factors. Psychotherapy, alone or in combination with pharmacotherapy is an effective treatment. Thus, if concomitant receipt of psychotherapy is not controlled for in a psychopharmacology trial, outcome may be biased. In this study, all peer reviewed journal articles describing the results of randomized, controlled psychopharmacology trials in two separate years were carefully reviewed to assess the possible influence of control versus lack of explicit control for effect of concomitant psychotherapy on clinical outcome. One hundred sixteen articles, published in the years 1996 and 2000, were reviewed. Those with categorically positive or non-positive global outcome were assessed for description of concomitant receipt of psychotherapy by subjects randomized to different pharmacotherapy treatments. Description of comparability in potentially confounding demographic and clinical variables was present in all studies. Only 22% of 89 studies meeting inclusion criteria explicitly controlled for concomitant psychotherapy. Seventy five percent of 20 studies that did, and only 46% of 69 studies that did not, found different outcomes in groups randomized to different pharmacotherapy interventions (p=.024). This result was not accounted for by other aspects of study design such as placebo-vs.-active control comparison, trial size, length, geographic location, number of sites or authors, source of funding, or diagnostic composition)-suggesting that uncontrolled receipt of psychotherapy may reduce likelihood of finding a difference between a new treatment and a control pharmacotherapy intervention. If confirmed by further investigation, the results may warrant adoption of relevant recommendations for controlled trial design in psychopharmacology research. The method used in this report may be useful in other areas of controlled trial research to assess influence of confounding variables.

Background: previous research has been inconclusive about the nature of hemispheric asymmetry in emotional processing. Method: 13 patients with DSM-IV bipolar disorder received repeated QEEGs over 2 years in different mood states. Z-score measures of asymmetry were assessed. Results: asymmetry in frontotemporal slow-wave activity appeared to be in opposite directions in depression compared to mania/hypomania. Conclusions: mood change in bipolar disorder is associated with change in QEEG asymmetry. Limitations: study of larger numbers of more homogenous patients under similar conditions is needed. Clinical relevance: study of mood state-dependent asymmetry changes in bipolar disorder may lead to better understanding of hemispheric processing of emotion.