The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Mania following use of ibogaine: A case series.

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).

Deep brain stimulation of the amygdala for treatment-resistant combat post-traumatic stress disorder: Long-term results.

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.

Safety and efficacy of targeting the supplementary motor area with double-cone deep transcranial magnetic stimulation vs figure-eight coil in treatment of obsessive-compulsive disorder with comorbid major depressive disorder.

BACKGROUND AND OBJECTIVE: The Supplementary Motor Area (SMA), a relatively large brain structure predominantly located along the interhemispheric fissure, is an established target for repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Obsessive-Compulsive Disorder (OCD). We investigated the feasibility, safety, and efficacy of targeting SMA using a double-cone "deep" TMS coil compared to conventional figure-eight coil for treatment of OCD with comorbid Major Depressive Disorder (MDD). METHODS: Sixty-two patients with treatment-resistant OCD and comorbid MDD participated in the study. All patients received high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) with a figure-eight coil (MagVenture B70), followed by 1 Hz rTMS over the bilateral SMA using either the B70 (N = 25) or double-cone deep coil (MagVenture DB80) (n = 23) for 36 treatment sessions. Weekly clinical assessments were conducted. RESULTS: Subjects overall had significant reductions in OCD and depressive symptom severity at the primary endpoint. Subjects stimulated at SMA with the double-cone deep coil had statistically significantly lesser reductions in overall OCD and depression symptom severity compared to the figure-eight group. The intensity of stimulation at SMA was significantly greater with the double-cone deep than figure-eight coil and e-field modeling showed that it affected broader regions beyond SMA (off-target stimulation). There was no significant difference in reported tolerability between groups. CONCLUSIONS: SMA stimulation using either a double-cone deep or conventional figure-of-eight coil was safe and was associated with a significant reduction in comorbid OCD and depression symptoms, but the higher intensities of stimulation with the double-cone deep coil used in this study were significantly less clinically beneficial than figure-eight coil stimulation.

The role of sex and age in the differential efficacy of 10 Hz and intermittent theta-burst (iTBS) repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD).

BACKGROUND: Sex- and age-dependent outcome differences have been observed in treatment of Major Depressive Disorder (MDD), including 10 Hz repetitive Transcranial Magnetic Stimulation (rTMS). We examined whether there are sex- and age-dependent differences in outcome with intermittent Theta Burst Stimulation (iTBS), another rTMS protocol. METHODS: The relationship between biological sex, age, and treatment outcome was retrospectively examined among 414 patients with MDD treated with 10 Hz or iTBS rTMS. Linear mixed-effects modeling was used to examine the association between treatment and change in the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR30) score from baseline to treatments 10 and 30, with biological sex (M/F), protocol (iTBS/10 Hz), age (≥/<50 years old), and time (treatment 1/10/30) included as fixed effects. The three-way sex-protocol-time and age-protocol-time interactions were used to determine any differential relationships between protocol and outcome dependent on sex and age. Post-hoc t-tests were conducted to examine differences in improvement. RESULTS: There was a significant three-way sex-protocol-time interaction at treatments 10 (p = 0.016) and 30 (p = 0.031). Males showed significantly greater improvement with iTBS than females at treatments 10 (p = 0.041) and 30 (p = 0.035), while females showed numerically greater improvement with 10 Hz treatment. While there was not a significant three-way age-protocol-time interaction, there was a significant interaction between age (≥50 years old) and time at treatments 10 (p = 0.007) and 30 (p = 0.042), and among age, sex, and time at treatment 30 (p = 0.028). LIMITATIONS: Retrospective naturalistic treatment protocol. CONCLUSIONS: iTBS appeared less efficacious in females than in males, and rTMS overall was more efficacious in patients over fifty, particularly females.

A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5-9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.

A comparison of self- and observer-rated scales for detecting clinical improvement during repetitive transcranial stimulation (rTMS) treatment of depression.

Clinical outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) for treatment of Major Depressive Disorder (MDD) vary widely, and no single mood rating scale is standard for assessing rTMS outcomes. This study of 708 subjects undergoing clinical rTMS compared the performance of four scales in measuring symptom change during rTMS treatment. Self-report and observer ratings were examined weekly with the Inventory of Depressive Symptomatology 30-item (IDS), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item (POMS), and Hamilton Depression Rating Scale 17-item (HDRS). While all scales were correlated and detected significant improvement, the degree of improvement over time as well as response (33-50%) and remission (20-24%) rates varied significantly. Higher baseline severity was associated with lower likelihood of remission, and greater improvement by sessions 5 and 10 predicted response across all scales. Use of only a single scale to assess outcome conferred 14-36% risk of failing to detect response/remission indicated by another scale. The PHQ was most likely to indicate improvement and least likely to miss response or remission. These findings indicate that assessment of symptom burden during rTMS treatment may be most accurately assessed through use of multiple instruments.

Acute Effects and the Dreamy State Evoked by Deep Brain Electrical Stimulation of the Amygdala: Associations of the Amygdala in Human Dreaming, Consciousness, Emotions, and Creativity.

Accurate localization of complex human experiences such as emotions, dreaming, creativity, and consciousness to specific cerebral structures or neural networks has remained elusive despite technological advances. We report the use of acute deep brain stimulation (DBS) to evoke behavioral and emotional effects by applying electrical stimulation (ES) at various voltage strengths to the basolateral and central subnuclei of the amygdala in addition to the head of hippocampus (HC) for two subjects with medically refractory post-traumatic stress disorder (PTSD). Our results suggest that the amygdala could be a node in a neural network responsible for the generation of complex vivid mental imagery and integrated sensory experiences similar to John Hughlings Jackson's "dreamy state" and "double consciousness," which have been classically associated with temporal lobe epilepsy during uncinate seizures. That we were able to elicit similar vivid, dynamic, complex, bizarre, and original mental imagery with ES in non-epileptic subjects suggests that Jackson's seizure related "dreamy state" and "double consciousness" may arise from heightened innate brain mechanisms with the amygdala acting as a node in the neural network responsible for physiologic dreaming and creative functions. Furthermore, our subjects experienced different emotions with different stimulation strengths at various electrode contacts. Our results suggest that higher voltage stimulation of the amygdala and HC at 4-5 V leads to predominantly negative responses and 2-4 V stimulation showed inversely coupled positive and negative responses of the amygdala in either hemisphere which may imply hemispheric dominance of emotional valences without relation to handedness. Due to the unique and complex responses dependent on location and strength of stimulation, we advise that all patients receiving DBS of the amygdala undergo acute stimulation mapping in a monitored setting before selecting therapeutic parameters for chronic stimulation.

Theranostic pharmacology in PTSD: Neurobiology and timing.

Recent reviews and treatment guidelines regard trauma-focused cognitive-behavior therapies as the treatments of choice for chronic post-traumatic stress disorder (PTSD). However, many patients do not engage in this treatment when it is available, drop out before completion, or do not respond. Medications remain widely used, alone and in conjunction with psychotherapy, although the limitations of traditional monoamine-based pharmacotherapy are increasingly recognized. This article will review recent developments in psychopharmacology for PTSD, with a focus on current clinical data that apply putative neurobiologic mechanisms to medication use-i.e., a theranostic approach. A theranostic approach however, also requires consideration of timing, pre, peri or post trauma in conjunction with underlying dynamic processes affecting synaptic plasticity, the HPA axis, hippocampal activation, PFC-amygdala circuitry and fear memory.

Neuromodulatory treatments for post-traumatic stress disorder (PTSD).

Electroconvulsive therapy has been used successfully in some individuals with posttraumatic stress disorder (PTSD) whose symptoms have not improved with other treatments. But there are only a few reports. Meanwhile, an array of new neuromodulation strategies, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, trigeminal nerve stimulation, and deep brain stimulation have been developed and applied experimentally in the treatment of other psychiatric disorders. This article will review the clinical evidence and mechanistic basis for their use in PTSD.

Bipolar pharmacotherapy and suicidal behavior Part 3: impact of antipsychotics.

INTRODUCTION: Antipsychotics, particularly second generation agents, are widely used in bipolar disorder, but their effect on suicidal behavior in this population has not been systematically studied. 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. Comparison of rates of suicidal events during mood stabilizer monotherapy, antipsychotic monotherapy, and combination of mood stabilizer and antipsychotic. RESULTS: Non-lethal suicide event rates were 9.4 times greater (chi2=28.29, p<.0001) during antipsychotic monotherapy and 3.5 times greater during mood stabilizer+antipsychotic (chi2=15.13, p=0.0001) than during mood stabilizer monotherapy. LIMITATIONS: Antipsychotics may have been prescribed because patients were at greater risk of suicidal behavior. First and second generation antipsychotics were not distinguished. CONCLUSIONS: Treatment of bipolar patients with antipsychotics is associated with an increase in non-lethal suicidal behavior. Thus, use of antipsychotics for bipolar patients requires careful monitoring for suicidal behavior. Further studies are urgently needed to better characterize this relationship.

Bipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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; p<0.0002). On compared with off treatment differences were similar for the three different agents. LIMITATIONS: Treatments were uncontrolled in this naturalistic setting, and data were analyzed retrospectively. CONCLUSIONS: 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.

Bipolar pharmacotherapy and suicidal behavior Part 2. The impact of antidepressants.

UNLABELLED: 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.

Neuromodulation for Treatment-Refractory PTSD.

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor and is now reducing PTSD symptoms in the first patient enrolled in an early-phase safety trial.

Treatment-refractory posttraumatic stress disorder (TRPTSD): a review and framework for the future.

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.

Deep Brain Stimulation of the Basolateral Amygdala: Targeting Technique and Electrodiagnostic Findings.

The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety.

Psychotherapy in controlled psychopharmacology trials. Does it matter if we ignore it?

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.

Lithium, anticonvulsants and suicidal behavior in bipolar disorder.

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.

The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression.

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.