Neurostimulatory and ablative treatment options in major depressive disorder: a systematic review

Depression is a nosologic entity that has afflicted humankind throughout its existence. The first description of a depressive state was made at the era of Hellenic enlightenment by Hippocrates, derived from one of the four humors, the melancholia. In ancient times, brain surgery was performed to treat mental problems in order to exorcise or appease spirits and ghosts. In 1888, the psychiatrist Gottlieb Burkhardt performed one of the first psychosurgical interventions through cortical excisions with the intention to treat a diagnosed mental illness, schizophrenia in that case. Even though the majority of his patients improved, one of them died, and many others presented serious complications due to the procedure [110]. Consequently, his results were interpreted as careless and unreliable, leaving place to almost 50 years without any related attempt to treat the medically refractory cases. It was not until 1936 that António Egas Moniz, in collaboration with Almeida Lima, brought in modern psychosurgery with apparent better results; these contributions to science led Moniz to receive the Nobel Prize in 1949 [78]. Together, they developed the technique of prefrontal leucotomy to treat severe mental disorders, based on previous studies in primates performed by Fulton and Jacobsen, where frontal lobes were completely removed in two chimpanzees [39]. A few years later, Walter Freeman and James Watts performed lobotomies on numerous cases and popularized this procedure. They even introduced a novel orbital approach with the use of the so-called ice-pick leucotome [37, 38, 118]. Until the 1950s, thousands of lobotomies were carried out around the globe, but the first discordances started to come out when scientific evidence showed no evident benefit of the surgery and, in some cases, even worsening of symptoms. In parallel, ECT was developed and was considered to be a revolutionary technique indicated for acute episodes of severe depression [12]. However, the broad clinical introduction of antipsychotics and antidepressants in the sixties led to a vast decrease in the use of surgical and electroconvulsive procedures for some decades, until the end of the past century.

In recent years, increased interest in psychiatric disorders and the introduction of worldwide accepted, standardized clinical guidelines have made it possible to perform an accurate diagnosis of the illness. Ethical committees have led to stricter diagnostic criteria and a more scientific approach of epidemiological studies. In recent history, newer techniques have also been developed; in the last decades, the novel interventions such as VNS, TMS, and DBS have been added as treating options for MDD. The surgical techniques have become more precise, safer, and more importantly nonlesional.

ECT was introduced in the late 1930s and was very rapidly accepted because of its effectiveness in severe psychiatric disorders. After years of animal experiments by Lucio Bini and Ugo Cerletti, the first patient was successfully treated in 1938 with constant alternant current electrical pulses over 200 V [12, 13, 19, 28]. Even though ECT was originally introduced for schizophrenia solely, this technique was widely used for almost all mental illnesses after a short period of time. Subsequently, when the method gained an ample recognition, the indications, contraindications, and search for proper parameters of stimulation were the subjects of investigation. In the 1950s, ECT and other therapeutic options for the time were eclipsed by the arrival of psychiatric pharmacotherapies; nonetheless, it showed its usefulness again many years later, by being effective in pharmacologically resistant patients [32, 82].

Nowadays, after grand stigmatization for decades, ECT prevails as one of the most effective therapies in the treatment of severe depressive events; it can reach an effect of up to 80% [32]. The repetition of this therapy should only be considered in patients who responded well to previous acute sessions [2]. Unfortunately, the benefit is usually not long lasting [36]. This procedure will probably remain a viable therapeutic option in medically resistant patients. It should never be considered as a first treatment alternative, which remains pharmacotherapy, due to its costs and temporary documented side effects like confusion and retrograde and/or anterograde amnesia [30].

VNS was first introduced as an experimental anticonvulsant procedure in dogs by Jacob Zabara in 1985 [123, 124]. A few years later, Kiffin Penry and Dean treated the first human case with VNS in order to treat epilepsy [87]. After several successful studies of epilepsy conducted in numerous centers, the pioneer case with treatment-refractory depression (TRD) as the indication for VNS was presented by Rush et al. at the end of the 1990s [40, 95]. The rationale was based on the beneficial effects on depressive symptoms in patients who had previously received VNS for seizures, but the exact mechanism of action was not known [26, 43, 49]. Long-term studies have proven the good clinical outcome of VNS for MDD while it is well tolerated; a successful response have been described in half of the patients, with complete remission in one third [40, 95, 96, 102]. Even though its mechanism of action is not completely clarified, immunohistological (in animals) and imaging (in TRD patients) studies have endorsed its clinical effect [81, 85]. It is believed that once the input information from the vagus nerve project into the solitary tract nucleus, it follows an ascending pathway to modulate various structures such as the amygdala, dorsal raphe, locus coeruleus, and the ventromedial prefrontal cortex that produces the effect over mood in patients [85].

Further research is required to elucidate the specific action of VNS, considering the anatomy of the vagus nerve with its projections. Moreover, cost-effectiveness studies are still lacking. Something to keep in mind is that immediately postoperatively and at short-term follow-up, VNS has shown a low effectiveness [76, 102]. However, its beneficial effect at long-term in a substantial amount of patients, together with its low number of unwanted side effects, make this method an attractive treatment for patients suffering from MDD.

TMS is an innovative technique and highly appealing to scientists and patients because of its noninvasive nature. TMS directly modulates superficial areas of the brain. It has been recently developed, and several theories about its mechanism of action have been proposed; induction of neurotransmitter release that alters brain physiology and neuronal depolarization seem to be the most important elements, but more data are required to confirm these statements [10, 11, 84]. In recent times, animal and clinical models have been used trying to understand the antidepressant effects of TMS [33, 34, 52‐54, 103]; functional imaging has demonstrated specific changes induced by TMS in brain metabolism, perfusion, and interconnections [23].

High-frequency TMS of the left dorsolateral prefrontal cortex has shown effectiveness in almost one third of pharmacotherapy-resistant MDD patients, always with significant differences compared with sham stimulation [6, 83]. Furthermore, differential opposite effects on depressive behavior have been observed when low versus high frequencies were compared [60, 108]. TMS is a safe procedure with no apparent structural damage after usage for several weeks; some of its advantages are its great tolerance in all patients, the lack of cognitive deterioration, or any other unwanted side effects. However, many questions regarding its mechanism of action have to be answered before expanding its use or indications. Another limitation is the duration of the effect, reflected on a worsening of depressive symptoms only 3 weeks after stimulation. This could represent a serious restraint since continuous stimulation is not possible with TMS.

Ablative surgery to treat mental illnesses is one of the therapies that has expanded more rapidly and widely as a nonpharmacological therapy. Throughout decades, many targets, approaches, and techniques have been tried, with diverse and sometimes contradictory outcomes. Although the effects on mood gained the attention of medical community, due to the growing prevalence and socioeconomic burden, often no objective measurement of the effects was performed, and probably misdiagnosed patients were included into the studies.

Since its successful application for tremor by Benabid et al. in 1987, DBS is applied on a large scale for movement disorders such as Parkinson's disease, tremor, and dystonia. For each indication, different targets and different theories have been developed with the intention to obtain the best clinical results. In DBS (mostly bilateral), electrodes are implanted in specific brain regions where high-frequency stimulation is applied. Its widely appreciated advantages over lesions are its reversibility and adjustability by manipulating the stimulation parameters. Apart from movement disorders, the applications in the last decade have been extended to psychiatric disorders such as Gilles de la Tourette syndrome and obsessive-compulsive disorder (OCD) [42, 68, 106, 117]. In a series of reports performed by Heath et al. between 1979 and 1981, cerebellar stimulation was applied for the treatment of various psychiatric pathologies including intractable depression, schizophrenia, psychiatric conditions secondary to epilepsy, psychotic behavior, and miscellaneous psychiatric symptomatology. Concerning the depressive cases, in five out of six patients, the symptomatology decreased significantly at maximum follow-up without medication. However, evaluation of clinical data is difficult to determine due to lack of standardized scales and absence of other updated reports [22, 44‐46]. More recently, DBS to treat MDD has followed diverse approaches in order to alleviate depressive symptoms.

In 2005, Mayberg et al. presented the first clinical study of DBS in depression. The hypothesis to stimulate this area was acquired from observations that showed hyperactivity of the subgenual cingulate cortex (Brodmann area 25; Cg25) in chronic depressed patients. It was thought that this area plays a primary role in processes like learning, memory, motivation, and reward—behaviors that change with depression. In this novel study by Mayberg et al., six patients were implanted and stimulated with parameters adjusted to the apparent optimal benefit. After 6 months, in 67% of patients, a reduction of more than 50% on the Hamilton depression rating scale (HDRS) was seen, with a total or partial remission in three patients. Clinically, improvement was referred as an increase in energy, interest, psychomotor speed, and decrease of apathy and anhedonia. In addition, imaging studies showed normalization in the cerebral blood flow of Cg25 and other areas which appear to be related with depression [73].

After this first study, two case reports concerning DBS for depression in different targets were published. In the first report, Jiménez et al. described considerable improvement after DBS of the inferior thalamic peduncle in a 49-year-old woman with a history of recurrent episodes of major depression for over 20 years. After 24 months follow-up of double-blinded stimulation, the score on the HDRS decreased significantly. After a 2-month double-blinded OFF stimulation period, there was an evident worsening of symptomatology with an increase on depressive scales, suggesting that the positive effect was obtained by DBS and not due to a placebo effect [51]. In the second report, Kosel et al. described the case of a 62-year-old woman with treatment refractory MDD with comorbid neuroleptic-induced tardive dyskinesias. DBS of the globus pallidus internus induced an evident drop in the HDRS score after stimulation [64]. Schlaepfer et al. published the positive results of DBS of the nucleus accumbens for depression in three patients, with an immediate effect on depressive ratings. Double-blinded periods with stimulation ON and OFF demonstrated a beneficial outcome only when ON stimulation was applied. Moreover, the positive behavioral changes in these patients were supported by positron emission tomography imaging that correlated symptomatology with an augmentation of metabolism in the nucleus accumbens, amygdala, and dorsolateral and dorsomedial prefrontal cortex, and reduced metabolism in the ventral and ventrolateral medial prefrontal cortex [101]. On the other hand, Aouizerate et al. implanted electrodes in two patients with a history of MDD and OCD. After clinical evaluations, they concluded that the best target for DBS to alleviate OCD symptoms was the ventral caudate, and for the best outcome in depression, the nucleus accumbens was pointed as the best option [3]. In a recent study, Sartorius et al. reported on the case of a 64-year-old woman with history of TRD for over four decades treated with DBS in the lateral habenula. After electrode implantation, the patient presented two relapses, one attributable to initial adjustment of parameters and the second probably due to a traumatism. When the proper functioning of the stimulator was demonstrated, complete remission was achieved for several weeks. After 60 weeks of DBS, the patient remained with an HDRS score of 0 without reported complications or side effects [100].

Nowadays, six main DBS targets of interest remain that have been reported (Table 2). Neuromodulation could be one of the most efficient techniques for this disorder due to the fluctuant behavior of patients and the high co-morbidity that accompanies this condition. Analysis of DBS results of the mentioned targets shows promising responses and evident positive outcomes with minimal side effects. Nevertheless, cost-benefit analysis and good selection of patients are indispensable matters for a successful result.

Novel stimulatory techniques are being developed using minimal invasive techniques. In this respect, DBS seems to be one of the most promising procedures due to its reversibility. DBS also offers the possibility to control the therapeutic effect by simply switching off the stimulation, which is usually not easily possible in other treatments. The main problem of DBS in MDD is at the moment the diversity of potential targets, varying from the cortex to the habenula. One way of solving this problem is to elucidate the mechanism of action of DBS in MDD by using computational and animal models.