Subgenual Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

Overview of MDD

Major depressive disorder (MDD) is a common psychiatric complaint with a lifetime prevalence of 17% ( ), affecting some 5% of the world’s population at any given time ( ). It is characterized by one or more prolonged episodes of severe sadness and/or melancholia with a tendency to relapse over time ( ), and is associated with significant morbidity and mortality (including a 10%–15% suicide rate) which persists in periods of euthymia ( ). The resulting costs to both the patient and society, including direct medical costs, suicide-related costs, unemployment, absenteeism, and reduced performance at work, are staggering. According to a recent study, the incremental economic burden of MDD in the United States alone was greater than $80 billion in 2010; when comorbid conditions were included, this estimate surpassed $210 billion ( ). Moreover, MDD is the second-highest cause of years lived with disability worldwide, after low-back pain ( ). Thus timely, effective, and durable treatments for MDD are needed to defray these substantial human and monetary costs.

Diagnosis of MDD

MDD is a heterogeneous syndrome which is thought to be the common final pathway of multiple pathophysiological processes. Studies to date have failed to identify biomarkers which might reliably distinguish subtypes of MDD. Thus, its diagnosis remains phenomenological—determined by the presence of a particular clinical phenotype. According to the recently released fifth edition of the Diagnostics and Statistics Manual (DSM-V) ( ), the diagnosis of MDD is defined by one or more major depressive episodes, the criteria for which are the presence of five or more of nine specified symptoms over the same 2-week period: depressed mood, markedly diminished interest or pleasure, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, and recurrent thoughts of death or suicidal ideation with or without a specific plan or suicide attempt; at least one of the symptoms must be either depressed mood or anhedonia. Moreover, these symptoms must represent a change from previous functioning, be present most of the time nearly every day, cause clinically significant distress or impairment in social, occupational, or other important areas of activity, and not be attributable to the physiological effects of a substance or another medical condition. Lastly, MDD can only be diagnosed in the lifetime absence of mania or hypomania, and provided depressive episodes cannot be better explained by the diagnosis of a schizophrenia spectrum or psychotic disorder.

Antidepressants and Psychotherapy

For the majority of patients with MDD, treatment consists of lifelong antidepressant pharmacotherapy and/or cognitive behavior therapy (CBT) ( ). Timing is critical, in that early intervention improves long-term outcomes while multiple untreated episodes may worsen the course of the illness such that it becomes resistant to treatment as the disease progresses ( ). Unfortunately, incomplete response to first-line measures occurs in up to one-third of patients and is predictive of poor response to additional treatments, including switching medications or augmentation with medications of the same or different class ( ). Underscoring this problem, a large multicenter clinical trial was conducted to determine whether response rates improved with a structured, stepwise approach to the treatment of MDD—the sequenced treatment alternatives to relieve depression (STAR∗D) trial ( ). Patients were initially treated with the selective serotonin reuptake inhibitor (SSRI) citalopram, and those who failed to achieve remission or were unable to tolerate this medication were offered a choice between switching to a different medication or adding on to their existing therapy (including the option of switching to or adding CBT) in three subsequent steps. Citalopram was sufficient for remission in only 28% of patients and the rates of remission diminished with each subsequent step, such that by the fourth trial of antidepressant pharmacotherapy remission was achieved in only an additional 6% of patients ( ). Similarly, patients requiring successive pharmacological or psychological interventions to achieve remission had a higher rate of relapse, while those who exited the study without having achieved remission were at the greatest risk of recidivism ( ).

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is generally defined as failure to respond to at least two antidepressant treatments, as well as augmentation therapies and behavioral adjuncts, that have been administered at an effective dose for a sufficient duration ( ). As indicated above, this population appears to comprise at least two subsets of patients: those who truly fail to achieve remission of their depressive symptoms despite extensive trials, and others who relapse after achieving remission. Compared to MDD in general, TRD is associated with increased morbidity, mortality, and societal costs ( ). For these patients, electroconvulsive therapy (ECT) remains the most effective intervention currently available, with remission rates of 40% ( ). However, it is associated with cognitive side-effects including short-term memory impairment, and relapse is common ( ). As an alternative to ECT, repetitive transcranial magnetic stimulation (rTMS) is associated with minimal side-effects but has modest short-term antidepressant effects ( ), particularly in patients with demonstrated failure to respond to conventional antidepressant medications ( ). Finally, vagal nerve stimulation appears to be effective in a small but significant subset of patients with TRD ( ). However, for patients where all options have failed, a surgical intervention to target abnormal nuclei, tracts, or networks in the brain directly may be considered.

Ablative Surgery

The surgical management of depression is fraught with controversy. The first explicit attempt to treat mental illness surgically in the modern surgical era was made in 1888 by the psychiatrist Gottlieb Burkhardt, who performed cortical excisions in one patient with mania, one with dementia, and four with primary paranoid psychosis, or schizophrenia, with decidedly mixed results ( ). In John Fulton and Carlyle Jacobson presented their seminal findings following ablation of the frontal cortices in primates, demonstrating that the animals showed less “experimental neurosis” to task failures, although they were also less able to complete the tasks successfully. Based on this work, Egaz Moniz, working in collaboration with the surgeon Pedro Almeida Lima, introduced prefrontal leucotomy/lobotomy for the treatment of psychotic disorders in 1936 ( ). This procedure initially entailed injecting pure ethyl alcohol into the prefrontal cortex (PFC) through bifrontal burr-hole craniostomies to interrupt the connections between the thalamus and the PFC; subsequent procedures involved the use of a leucotomy for the same purpose. At a time when few alternatives existed for these severe mental illnesses, they described “worthwhile improvement” in 14 of 20 severely ill patients ( ). The frontal lobotomy was further refined by , and in an effort to make the surgery more accessible, Freeman went on to develop and popularize transorbital leucotomy for the treatment of a diverse array of psychiatric disturbances on an outpatient basis ( ). This procedure involved inserting an ice pick through the orbital roof into the basal frontal lobe, and sweeping it in a defined manner to sever the same thalamo–cortical and cortico–thalamic connections. Well over 50,000 such procedures were conducted worldwide in the decade following 1945 despite numerous side-effects, including epilepsy, personality changes, urinary incontinence, and a mortality rate of approximately 4% ( ). Reportedly, some measure of improvement was seen in 60% of patients with affective, psychotic, and other mental disorders, although these studies are limited by the absence of well-defined diagnostic groups. By the late 1950s overuse and unacceptably high long-term morbidity drove this procedure out of favor, and it was eventually abandoned with the advent of antipsychotic and antidepressant medications ( ).

Despite the notoriety of these interventions, interest in the surgical management of severe refractory mental illness persisted, with authors seeking to refine the extent of the disconnection to limit complications and side-effects. Stereotactic techniques were pioneered in the early 1900s ( ), and in 1949 William Scoville described a technique for sectioning the orbitofrontal cortex to a thickness of 1 cm from the base of the skull ( ). This disconnection was subsequently refined by Geoffrey Knight into the procedure known as subcaudate tractotomy, corresponding to bifrontal lesions located beneath and in front of the head of the caudate nucleus. Initially this procedure entailed the stereotactic insertion of radioactive yttrium rods into the brain ( ), and resulted in complete recovery or marked improvement in 68% of patients with severe depression ( ). Later, radiofrequency ablation was employed with comparable results ( ).

Another target for ablative surgery is the cingulate gyrus—either alone, or combined with subcaudate tractotomy in a procedure called limbic leucotomy. The cingulate gyrus is a key element of the limbic system, which was first described in by James Papez as being integral to emotional experience and expression. This suggested its importance in affective disorders, and thereafter Fulton proposed the anterior cingulate as a potential target for psychosurgical intervention ( ). Ablative surgeries soon followed, with Jacques Le Beau being the first to describe cingulotomy as a treatment of psychiatric disorders in 1949. This procedure constitutes the creation of a lesion in a region approximately 15–20 mm posterior to the anteriormost point of the frontal horns of the lateral ventricles ( ). Interestingly, using this technique Le Beau found no improvement in five depressive patients with anxiety and pain, but good results in three out of four patients with depression and obsessive neurosis ( ). Thomas Ballantine, who was the first to describe stereotactic anterior cingulotomy for psychiatric disorders, found that 62% of patients with severe affective disorders comprising unipolar ( n = 83) or bipolar ( n = 23) depression and schizoaffective disorder ( n = 14) had worthwhile improvement following this procedure ( ), with personality changes, epilepsy, weight gain, and urinary incontinence as potential side-effects ( ). A more recent study suggests that as many as 76% of carefully selected MDD patients may derive at least some benefit from anterior cingulotomy ( ). The most common target for these procedures is typically the dorsal anterior cingulate gyrus, corresponding to Brodmann’s area (BA) 24, and the adjacent fibers of the cingulum. Interestingly, better outcomes have been associated with smaller, more rostral lesions ( ). Subrostral cingulotomies, consisting of lesions to the cingulate gyrus ventral to the genu of the corpus callosum, have also been conducted over the years with variable outcomes in patients with depression ( ).