Peter Giacobbe

Treatment Resistant Depression— Advances in Somatic Therapies

BACKGROUNDnThe failure to achieve remission for patients with Major Depressive Disorder (MDD) represents a major public health concern. Inadequately treated depression is associated with higher rates of relapse, poorer quality of life, deleterious personal and societal economic ramifications, as well as increased mortality rates. Unfortunately, only a minority of patients achieves this goal with initial antidepressant treatment and by convention, failure to achieve response after two adequate trials of antidepressant therapy defines Treatment Resistant Depression (TRD). Furthermore, results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) group of studies suggest that approximately 50% of real world patients who meet criteria for MDD fail to achieve remission, even after four carefully monitored sequenced treatments.nnnMETHODSnGiven these limitations of existing antidepressant medications alone and in combination, together with improved understanding of the neural circuitry of depression, it is not surprising that there is a renewed interest in neuromodulation strategies for TRD.nnnRESULTSnThe purpose of this article is to review the evidence for the inclusion of various non-pharmacological, neuromodulatory strategies for TRD. Specifically, information regarding the mechanism, tolerability and efficacy of electroconvulsive therapy (ECT), magnetic seizure therapy (MST), repetitive transcranial magnetic stimulation (rTMS), vagal nerve stimulation (VNS), and deep brain stimulation (DBS) in ameliorating TRD will be presented.nnnCONCLUSIONSnAlthough these treatments are at various stages of clinical development, they represent a new frontier in expanding the treatment options available for individuals with TRD, as well as contributing to a better understanding the neurobiology of depressive disorders.

Effectiveness and acceptability of deep brain stimulation (DBS) of the subgenual cingulate cortex for treatment-resistant depression: A systematic review and exploratory meta-analysis

BACKGROUNDnDeep brain stimulation (DBS) applied to the subgenual cingulate cortex (SCC) has been recently investigated as a potential treatment for severe and chronic treatment-resistant depression (TRD). Given its invasive and experimental nature, a comprehensive evaluation of its effectiveness and acceptability is of paramount importance. Therefore, we conducted the present systematic review and exploratory meta-analysis.nnnMETHODSnWe searched the literature for English language prospective clinical trials on DBS of the SCC for TRD from 1999 through December 2012 using MEDLINE, EMBASE, PsycINFO, CENTRAL and SCOPUS, and performed a random effects exploratory meta-analysis using Event Rates and Hedges׳ g effect sizes.nnnRESULTSnData from 4 observational studies were included, totaling 66 subjects with severe and chronic TRD. Twelve-month response and remission rates following DBS treatment were 39.9% (95% CI=28.4% to 52.8%) and 26.3% (95% CI=13% to 45.9%), respectively. Also, depression scores at 12 months post-DBS were significantly reduced (i.e., pooled Hedges׳ g effect size=-1.89 [95% CI=-2.64 to -1.15, p<0.0001]). Also, there was a significant decrease in depression scores between 3 and 6 months (Hedges׳ g=-0.27, p=0.003), but no significant changes from months 6 to 12. Finally, dropout rates at 12 months were 10.8% (95% CI=4.3% to 24.4%).nnnLIMITATIONSnSmall number of included studies (most of which were open label), and limited long-term effectiveness data.nnnCONCLUSIONSnDBS applied to the SCC seems to be associated with relatively large response and remission rates in the short- and medium- to long-term in patients with severe TRD. Also, its maximal antidepressant effects are mostly observed within the first 6 months after device implantation. Nevertheless, these findings are clearly preliminary and future controlled trials should include larger and more representative samples, and focus on the identification of optimal neuroanatomical sites and stimulation parameters.

Neurostimulation therapies for treatment resistant depression: A focus on vagus nerve stimulation and deep brain stimulation

Antidepressant treatments, including pharmacotherapy and psychotherapy, do not result in remission for the majority of patients with major depressive disorder. The high prevalence of treatment resistant depression (TRD) poses a significant issue for patients as well as both societal and economic costs. Due to the limited efficacy of existing therapies in this sub-population, alternative somatic treatments are being explored. Both vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are neurostimulation treatments for TRD. While VNS has Food Drug Administration approval as an adjunctive therapy for MDD, DBS is still in the experimental stages. This article will review the evidence supporting the clinical utility of these therapies.

Neurosurgical treatment of bipolar depression: defining treatment resistance and identifying surgical targets

OBJECTIVESnBipolar disorder (BD) is a complex psychiatric disorder that is often underrecognized, misdiagnosed, and challenging to detect. During the past decade, substantial progress has been made in the development of pharmacotherapeutic and psychosocial interventions for various phases of BD. Notwithstanding these developments, the majority of BD individuals, and particularly patients with bipolar depression, receiving guideline concordant care do not experience syndromal or functional recovery, underscoring the need for novel treatments. Early success with deep brain stimulation (DBS) in the treatment of major depressive episodes as part of major depressive disorder (MDD) has provided the impetus to explore its application in other treatment-resistant psychiatric disorders, notably BD. Herein, we provide the rationale for employing DBS as an alternative treatment avenue in individuals with bipolar depression.nnnMETHODSnWe conducted a PubMed literature search, focusing on English language articles beginning in 1950 to the present day, and employed the following search terms: bipolar disorder, neurosurgery, deep brain stimulation, neuroimaging, and circuitry. Search results were then manually reviewed and relevant articles selected for analysis. Relevance was determined by author consensus and overall manuscript quality. We also reviewed articles on currently available treatment options for BD in order to develop a coherent and practical definition of treatment resistance with a focus on surgical intervention.nnnRESULTSnSeveral lines of evidence indicate that although mania is the defining feature of bipolar I disorder, depressive symptoms and episodes dominate the longitudinal course, account for most of the illness burden including premature mortality, and are least responsive to contemporary treatments. Disease models in bipolar depression implicate abnormalities in the structure and function of discrete neural circuits that subserve affective processing and cognitive function with the subgenual cingulate cortex occupying a central role. Modulation of the cingulate cortex with DBS in treatment-resistant MDD populations has proven to offer acute and sustained antidepressant effects, suggesting possible benefits for other mood disorder populations.nnnCONCLUSIONSnA surgical intervention for bipolar depression would not only be a proof of concept regarding disease modeling but also an important and novel treatment avenue for individuals affected by bipolar depression.

Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial

BACKGROUNDnAnorexia nervosa is a life-threatening illness. Brain circuits believed to drive anorexia nervosa symptoms can be accessed with surgical techniques such as deep brain stimulation (DBS). Initial results suggest that DBS of the subcallosal cingulate is safe and associated with improvements in mood and anxiety. Here, we investigated the safety, clinical, and neuroimaging outcomes of DBS of the subcallosal cingulate in a group of patients during 12 months of active stimulation.nnnMETHODSnWe did this prospective open-label trial at the Department of Surgery of the University of Toronto (Toronto, ON, Canada). Patients were eligible to participate if they were aged 20-60 years and had a diagnosis of anorexia nervosa (restricting or binge-purging subtype) and a demonstrated history of chronicity or treatment resistance. Following a period of medical stabilisation, patients underwent surgery for DBS and received open-label continuous stimulation for the entire 1 year study duration. The primary outcome was safety and acceptability of the procedure. The secondary outcomes were body-mass index (BMI), mood, anxiety, affective regulation, and anorexia nervosa-specific behaviours at 12 months after surgery, as well as changes in neural circuitry (measured with PET imaging of cerebral glucose metabolism at baseline and at 6 and 12 months after surgery). This trial was registered with ClinicalTrials.gov, number NCT01476540.nnnFINDINGSn16 patients with treatment-refractory anorexia nervosa were enrolled between September, 2011, and January, 2014, and underwent DBS of the subcallosal cingulate between November, 2011, and April, 2014. Patients had a mean age of 34 years (SD 8) and average illness duration of 18 years (SD 6). Two patients requested that their devices be removed or deactivated during the study, although their reasons for doing so were poorly defined. The most common adverse event was pain related to surgical incision or positioning that required oral analgesics for longer than 3-4 days after surgery (five [31%] of 16 patients). Seven (44%) of 16 patients had serious adverse events, most of which were related to the underlying illness, including electrolyte disturbances. Average BMI at surgery was 13·83 (SD 1·49) and 14 (88%) of the 16 patients had comorbid mood disorders, anxiety disorders, or both. Mean BMI after 12 months of stimulation was 17·34 (SD 3·40; p=0·0009 vs baseline). DBS was associated with significant improvements in measures of depression (mean Hamilton Depression Rating Scale scores 19·40 [SD 6·76] at baseline vs 8·79 [7·64] at 12 months; p=0·00015), anxiety (mean Beck Anxiety Inventory score 38·00 [15·55] vs 27·14 [18·39]; p=0·035), and affective regulation (mean Dysfunction in Emotional Regulation Scale score 131·80 [22·04] vs 104·36 [31·27]; p=0·019). We detected significant changes in cerebral glucose metabolism in key anorexia nervosa-related structures at both 6 months and 12 months of ongoing brain stimulation.nnnINTERPRETATIONnIn patients with chronic treatment-refractory anorexia nervosa, DBS is well tolerated and is associated with significant and sustained improvements in affective symptoms, BMI, and changes in neural circuitry at 12 months after surgery.nnnFUNDINGnKlarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.

Neurosurgical Treatment of Anorexia Nervosa: Review of the Literature from Leucotomy to Deep Brain Stimulation

This paper reviews the literature on the surgical treatment of refractory anorexia nervosa (AN) and examines how this literature can inform current circuit models of the disease. The literature contains reports of 35 patients undergoing a neurosurgical procedure for the specific treatment of refractory AN, with the first reported operation, a lobotomy, in 1950. All patients were deemed treatment resistant according to contemporary standards, with the nature of the procedure changing with evolving surgical techniques and methods. All procedures targeted the limbic system and, in a majority of cases, were associated with reported symptomatic improvement. Neurosurgery in AN has been, and continues to be, reserved for patients with chronic and life-threatening illness, for whom conventional treatment has failed. Early procedures, which were viewed as life-saving measures, were crude by todays standards but targeted anatomic structures and pathways implicated in modern models of AN. The last decade has seen a concerted effort in elucidating the neurocircuitry underlying prominent etiologic and maintaining factors in AN, including mood, anxiety and dysfunctional reward processing. This has translated into the development of novel, focused therapeutic options for patients with treatment-refractory AN.

Deep Brain Stimulation Modulates Gamma Oscillations and Theta-Gamma Coupling in Treatment Resistant Depression.

BACKGROUNDnDeep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG) is becoming an effective therapeutic option for treatment resistant depression (TRD).nnnOBJECTIVE/HYPOTHESISnIdentifying the neurophysiological mechanisms altered by DBS may lead to more tailored treatment parameters and enhanced efficacy.nnnMETHODSnTwenty TRD patients with implanted DBS in the SCG were recruited. Patients participated in three EEG recording sessions, one with DBS ON, one with DBS randomized to ON or OFF, and one with DBS OFF. During each session, subjects performed N-back working memory tasks, namely the 0-back and 3-back. Fourteen subjects with valid EEG were included in the analysis. Changes in frontal gamma oscillations (30-50 Hz) and coupling between theta (4-7 Hz) and gamma oscillations as a result of DBS stimulation were quantified and correlated with depressive symptoms.nnnRESULTSnDBS stimulation resulted in suppression of frontal oscillations in the ON state relative to the OFF state during the N-back tasks. Greatest suppression was demonstrated in beta and gamma oscillations and most pronounced during the 3-back. Suppression of gamma oscillations in the 3-back correlated with a reduction in depressive symptoms. DBS ON relative to OFF in the 3-back also resulted in an increase in theta-gamma coupling that correlated with a reduction in depressive symptoms.nnnCONCLUSIONnSuppression of gamma oscillations and increased theta-gamma coupling through DBS is likely mediated by both SCG activation of inhibitory circuits and an enhancement of plasticity in the frontal cortex. Activation of both pathways may explain the therapeutic properties of DBS in TRD.

Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study

BACKGROUND AND OBJECTIVEnBecause increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal.nnnMETHODnThis was a randomized, double-blind, placebo-controlled study of 48 patients who met criteria for DSM-IV(®) Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of ≥14. Half the participants received 0.25mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial.nnnRESULTSnOne week after stopping the medication, the HAMD ratings of the drug-treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend. One week after the medication was stopped, the Clinical Global Index fell 1.64±0.18 units for the medication-treated patients, compared to 1.12±0.26 units for the placebo group (P=0.05). The regimen was well tolerated.nnnCONCLUSIONSnSeven days of an ultra-low dose of 0.25mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidol-induced behavioural supersensitivity to dopamine.nnnLIMITATIONSnThe sample was small. More patients are needed in a future study.

Deep Brain Stimulation for the Management of Treatment-Refractory Major Depressive Disorder

Major Depressive Disorder (MDD) is among the most common psychiatric conditions, and is responsible for substantial human morbidity worldwide. The last two decades have seen significant progress in our understanding of the neural circuits driving MDD, which is now increasingly understood as a disorder of neural circuitry. The success of deep brain stimulation (DBS) as a modulator of circuit dysfunction in motor disorders such as Parkinson’s Disease has generated interest in it’s use in other circuit-based conditions, including MDD. The result has been resurgence in interest in surgery for refractory mood disorders, where advances in functional imaging have helped identify key anatomic targets as critical notes in the circuit. This chapter reviews the history of surgery for major depression, the rationale for focal neuromodulation in the condition, and provides a summary of the clinical experience of DBS in MDD to date.

The Nature and Treatment of Therapy-Resistant Depression

Therapy-resistant depression (TRD) is highly prevalent and has major health and economic implications. Although it is associated with psychiatric and medical comorbidity, there does not appear to be a