Method. ECT was developed in 1938 and is the oldest and best evaluated neuromodulation therapy for treatment-resistant depression. An electrical current is administered to the brain through the scalp. Seizures are induced under general anesthesia and muscle relaxation. Usually, a series of seizures (9–12) are given over several weeks, generally 2–3 treatments per week.

Mechanism of action. The mechanism of action is not understood, but the induction of a generalized seizure and the postictal suppression ^{12– 17} are important factors contributing to the antidepressant effect.

Clinical application. ECT is highly effective in treatment-resistant depressive disorders, with 50–80% of patients achieving remission ^{18, 19} , and is therefore the most effective acute treatment for major depressive disorder ^{20, 21} .

Efficacy. ECT has level I evidence for acute efficacy and relapse prevention, and level II for safety and tolerability ²² (see Table 1). Transient cognitive side effects, such as postictal confusion and anterograde amnesia, are frequent and more pronounced in bilateral electrode placement as compared to unilateral electrode placement ^{23, 24} . Up to 55% of patients report persistent negative cognitive side effects after ECT ²⁵ .

Ethical aspects. Although very well investigated, effective and safe, ECT is still an underused treatment in treatment-resistant depression ²⁶ for several reasons. ECT is still stigmatized because of its different use in the past ^{27, 28} and cognitive side effects are often overestimated, in comparison to cognitive impairment due to depression itself. Clinical staff members are still inadequately trained and face prejudices, such as limitations on the use of ECT in elderly patients. This leads to a reduced availability in hospitals. The idea that every patient should have access to the treatment with the best prognosis is reflected in the ethical principle of justice. For ECT, the ethical principle of justice is not adequately met for the above mentioned reasons.

Current research and outlook. Research has focused on maximizing antidepressant efficacy while minimizing cognitive side effects. Thus, administration techniques (unilateral vs. bilateral stimulation, ultra-brief pulse-width stimulation), the role of postictal depression, depth of anesthesia ^{29, 30} , the separation of effects on cognition and depression ^{31– 33} , and the best algorithm for maintenance therapy are current research questions.

ECT is established as a conventional treatment in treatment-resistant depression with few contraindications. ECT therefore often serves as treatment for the comparison group in studies as the “gold standard” for the evaluation of new treatments (e.g., MST).

Method. In MST, seizures are induced with magnetic pulses. The clinical procedure (general anesthesia, 9–12 sessions) is similar to ECT. The aim of the development of MST was to minimize cognitive side effects through a more focal induction of seizures ³⁴ .

Mechanism of action. Similar to ECT, the exact mechanism of action is unknown. In MST, only the superficial cortex is exposed during seizure induction, but the seizure generalizes to broader brain regions ³⁵ . Imaging studies have found evidence for changes in glucose metabolism in brain regions that have frequently been reported as dysfunctional in depression ^{36– 38} .

Clinical application. Clinical application is limited to a few study centers worldwide, because a specially modified device is required.

Efficacy. Only data from open-label pilot studies with small sample sizes in a few research sites are actually available. Efficacy seems to be similar to ECT, but possibly with a superior side-effect profile regarding cognition ^{38– 43} (see Table 1).

Ethical aspects. As long as MST is applied in clinical studies with careful patient selection and information about alternative treatment options is available, the ethical principles of patient autonomy and well-being are fulfilled.

Actually, research in MST is completely controlled by a few companies because special devices are required. In spite of attractive results from small samples, research activities have seemed to diminish. The fear of cognitive side effects is one major obstacle to encouraging patients to undergo seizure therapy. Thus, the development and availability of a potential treatment method with a possible superior side-effect profile is delayed. This contravenes the ethical principle of patient well-being and justice.

Current research and outlook. Best stimulation parameters (e.g., finding the optimal stimulus intensity), the relevance of seizure threshold titration, and the development of devices and coils are current research foci. One controlled double-blind trial (n=20) is underway (Lisanby et al., see the Registry on ClinicalTrials.gov NCT00973934 https://clinicaltrials.gov/). Long-term blinded and controlled studies with larger samples, and studies into the evaluation of relapse rates and the role of maintenance MST are needed.

Method. Transcranial magnetic stimulation (TMS) is a noninvasive therapy option which can be applied to outpatients with treatment-resistant depression.

During repetitive TMS, a fast series of brief pulses of strong magnetic stimuli are applied to the brain. Deep repetitive TMS is a modification of repetitive TMS which can reach deeper cortical regions with a special coil ⁴⁴ . The H Coil ⁴⁵ is the only coil whose safety and effectiveness has been tested. This coil is able to change cortical excitability at a depth of up to 6 cm ⁴⁶ .

Mechanism of action. Repetitive TMS and deep repetitive TMS produce changes in neuronal excitability. The magnetic field generated at the coil passes unimpeded through the scalp and skull. An electrical current is induced in the underlying tissue which modulates neural activity ⁴⁷ . Depending on the parameters of stimulation, cortical excitability can be increased or decreased ⁴⁸ .

Clinical application. After the identification of the motor threshold, the coil is moved from the motor cortex to the specific target cortical region. In the treatment of major depressive disorder, the target area is usually the left dorsolateral prefrontal cortex ^{49– 51} . In contrast to ECT or MST, no general anesthesia is required. Patients and TMS operators should wear earplugs during TMS. Usually, 10–30 treatment sessions of 15–45 minutes are administered daily in an outpatient setting.

Efficacy. There is evidence for repetitive TMS either as a mono- or add-on therapy for the treatment of moderate treatment-resistant depression (evidence level I) ⁵² . In 2008, repetitive TMS was approved by the FDA for the treatment of moderate treatment-resistant depression.

Several studies have investigated the efficacy of deep repetitive TMS in patients suffering from treatment-resistant depression ^{49– 51, 53– 57} . Deep repetitive TMS seems to be an effective and safe treatment for patients with treatment-resistant depression (see Table 1).

Side effects. Overall, repetitive TMS is seen as safe without enduring side effects: no long-term neurological, cognitive, or cardiovascular side effects are reported ^{58– 61} . Transient headache is the most common side effect after repetitive TMS.

Similar to repetitive TMS, deep repetitive TMS is considered a safe treatment. Scalp discomfort, transient headache and dizziness, insomnia, perceiving an odd smell, numbness in the right temporal and right cervical zone, and (in single cases) generalized seizures have been reported ⁴⁴ .

There is no long-term evidence for either repetitive TMS or deep repetitive TMS because most studies are limited to 6–12 weeks (see 22 for a comprehensive review of TMS studies).

Ethical aspects. Although, the FDA has approved repetitive TMS (level I evidence for acute efficacy), this treatment is only available in special centers and patients do not have the opportunity to choose this therapy option even though its clinical evidence has been proven. Both repetitive TMS and deep repetitive TMS seem to have lower response rates in treatment-resistant depression as compared to ECT (Lipsman, Sankar et al. 2014), but the side-effect profile seems superior. In addition, TMS can be performed in an outpatient setting without anesthesia. Patients should be given the choice between a less effective but also less risky therapy, and a therapy with a higher risk for side effects and higher efficacy. This fits with the ethical criterion of justice and patient autonomy.

Current research and outlook. Current research foci in TMS are the effect of low- and high-frequency stimulation and laterality issues, and optimizing TMS pulse and train parameters, as well as the influence of the characteristics of the TMS pulse itself (with the help of the controllable pulse TMS device). Little is known about combination therapy (e.g., pharmacotherapy, psychotherapy).

Method. VNS is an invasive brain stimulation method. A small electrical pulse is administered with an implanted neurostimulator to a bipolar electrode, surgically implanted at the left vagus. The pulse generator is implanted under the skin of the left chest. Intermittent electrical currents are sent from the generator to the vagus nerve and via the nucleus tractus solitarius to various regions of the brain. Usually, electrical pulses that last about 30 seconds are forwarded about every 5 minutes from the generator to the vagus nerve; other parameters consist of a current intensity of 0.20 to 2.50 mA, a pulse width of 500 ms and a pulse frequency of 20 Hz.

Mechanism of action. Brain imaging studies have demonstrated metabolic changes in the prefrontal cortex and in limbic structures relevant to mood regulation ⁶² , possibly through the modulation of monoaminergic neurotransmission ⁶³ .

Clinical application. VNS, in its current form, is a chronic treatment. During the first months of treatment, the best stimulation parameters have to be selected; therefore, regular visits are required at the beginning of therapy. In the long-term, yearly checkups are advised to ensure the functioning of the device (e.g., battery exhaustion and lead connection) and to adjust parameters if necessary.

Efficacy. In 2005, the FDA-approved VNS therapy for the adjunctive long-term treatment of chronic or recurrent depression for those patients who have not had an adequate response to two or more antidepressant treatments.

Long-term effects were significantly superior by outcomes in comparison to patients receiving treatment as usual. However, VNS therapy is more effective in patients with moderate but not extreme levels of resistance ^{64, 65} (see Table 1).

Side effects. Possible side-effects of VNS therapy are: an infection at the device, a hoarse voice, cough, and shortness of breath, as well as difficulties in swallowing ^{64, 65} .

Ethical aspects. Although clinical efficacy has been proven and is superior to non-invasive treatments (e.g., repetitive TMS), VNS is not available for many patients as insurance companies only cover the cost for the surgery and not for the (psychiatric and neurosurgical) long-term treatment. For financial reasons, VNS is therefore unattractive to hospitals. This situation contravenes the criteria of justice, well-being and autonomy. In addition, the opportunity to conduct research is limited and important safety aspects (e.g., predictors of response and long-term side-effects) are not assessed sufficiently. This again contravenes the criterion of patient well-being.

Current research and outlook. Research in VNS is limited because of the above mentioned financial restraints. Predictors of response (prior response to ECT, age, subtypes of depression etc.) and long-term safety (above 3 years) can only be inferred from its use in the treatment of epilepsy.

Method. DBS is the most invasive neuromodulation technique because it involves the stereotactic implantation of unilateral or bilateral electrodes in the brain, connected to a permanently implanted, battery-powered neurostimulator. Usually, a pair of electrodes are placed into a specific brain region assumed to be involved in mood regulation. Constant stimulation can be adjusted with the parameters of voltage, pulse width, frequency and shape of the electric field.

Mechanism of action. The effect of DBS on the brain is far from being understood. Stimulation parameters (frequency, amplitude, pulse width, duration) also clearly have an impact on the effect. With commonly used parameters, a relatively large volume of neural tissue is influenced ⁶⁶ .

Functional neuroimaging data have demonstrated that DBS changes the activity of brain areas far beyond the targeted region. Thus complex neural networks are putatively modulated ^{66– 68} .

In hypothesis-guided approaches, several brain structures are targets of DBS: the subgenual cingulate gyrus (Cg25) ^{32, 67, 69} , the anterior limb of the capsula interna (ALIC) ^{70, 71} and the nucleus accumbens (Nacc) ^{68, 72} , and the supero-lateral branch of the medial forebrain bundle (slMFB) ⁷³ .

Clinical application. DBS is only available for a highly selected group of patients suffering from very therapy-resistant depression in clinical studies in a few centers worldwide. Launching a DBS study requires a specialized multidisciplinary team, including a psychiatrist, psychologist, and neurosurgeon, and the possibility for a long-term follow-up.

Efficacy. In small pilot studies, an antidepressant effect of DBS was described: a reduction of symptoms of greater than 50% was reached in about 50% of the patients after 12 months of DBS treatment ^{70, 74– 78} . First results have found superior response rates in the slMFB (more rapid effects and >70% response rates after 3 months ⁷⁹ and after 12 months ⁷⁹ ), but long-term data and larger samples are required for efficacy evaluation. First small studies with sham stimulation found conflicting results concerning placebo effects ^{79, 80} (see Table 1).

Side effects. The adverse reactions caused by DBS can be differentiated in first effects related to the surgical implantation procedure itself (e.g., bleeding, infection) and second effects related to the stimulation which depend on the target site of stimulation (e.g., paresthesia, muscle contraction, dysarthria, and diplopia, hypomania, anxiety). The former are rare (i.e., risk of seizure 1–3%, of bleeding 1–5%, and of infection 2–25%), the latter are reversible with a parameter adjustment. DBS seems to have neutral-to-positive effects regarding cognition ^{33, 74, 75} .

Ethical aspects. Few treatment approaches in psychiatry have initiated as much ethical debate as DBS. Major issues concerning patient autonomy are: the manipulation of human personality with DBS ⁸¹ , a sudden disruption of the patient’s biography ⁸² , and the ability of patients with treatment-resistant depression to give informed consent ⁸³ .

Regarding well-being, the induction of new psychiatric symptoms (e.g., hypomania symptoms ⁸⁴ or high-risk behavior ⁸⁵ ) is debatable. Because DBS is a high-risk intervention, patients have to be carefully selected and, as long as the optimal target has not been established and efficacy is questionable, only patients resistant to all conventional treatment approaches (including ECT) should be selected for studies. Careful individual risk-benefit ratios are necessary to ensure the criterion of patient well-being.

The idea of possibly enhancing cognitive functions is important in terms of the criterion of justice, although in treatment-resistant depression, the amelioration of cognitive functions could be discussed in relation to a prior dysfunction in cognition caused by the depression ⁸¹ .

DBS is only available in specialized centers for a few, highly selected, therapy-resistant patients. In addition, DBS is very expensive and dominated by a few companies, and little investment from the government exists. These factors restrict availability but should be seen in the light of patient well-being (e.g., to prevent harm from untrained staff, and random application before safety is assessed).

Current research and outlook. DBS is a treatment method in the early phase of evaluation (level III). Therefore, efficacy and safety have to be assessed in sham stimulation control designs. Due to ethical reasons, it is difficult to install a randomized design. Current research questions are the best target site, parameter adjustment protocols, the predictive value of acute stimulation effects, and other predictors of response (e.g., depression subclusters, length and number of depressive episodes, former response to ECT). Furthermore, imaging studies are necessary to elucidate the mode of action.