Despite new insights and evidence-based treatment options for clinical depression in the recent years, the current choices of safe and effective therapies are still inadequate to sustain a long-term response in the depressed patient. Many do not improve, improve partially or are classified as ‘treatment resistant’ with poor compliance and marked functional impairment. The aim of this article is to review future therapeutic options and advances in treatments available for this cohort of patients. Several innovative and promising studies are underway to explore the role of ketamine, a glutamate N-methyl-d-aspartate (NMDA) antagonist in treating treatment-resistant depression and acute suicidal ideation. Furthermore, new research reveals that depression is associated with a significant drop in neurotrophic factors such as brain derived neurotrophic factor (BDNF) and increasing BDNF may be a new strategy for developing new antidepressants. Neuromodulation interventions by stimulating specific brain regions including deep brain stimulation (DBS), magnetic seizure therapy (MST), and transcranial direct current stimulation (tDCS), still in experimental stages, are also discussed.
The course of depressive illness causes a disruption to personal life, hinders relationships, increases the risk of suicidal behavior and is a substantial burden to the economy. Current treatment with standard antidepressants, which are serotonin or norepinephrine based, psychotherapy or electro-convulsive therapy (ECT), may take weeks to months for symptom resolution. Recent scientific advances in understanding mood regulation, neurochemicals, receptor modulation and the illness itself, have led to a number of potential approaches to managing treatment resistant depression (TRD) earlier in the course of development. It is expected that next generation antidepressants will work within hours to days to produce rapid therapeutic effects and eliminate suicidal ideation with instantaneous treatment.1
N-METHYL-D-ASPARTATE (NMDA) RECEPTORS
Based on early animal studies, it was postulated that the glutamatergic system, most notably the NMDA system, played a role in the pathophysiology of mood disorders, indicating that this may be a target for treatment.2 Glutamate is the primary excitatory neurotransmitter in the brain that binds to NMDA receptors. A growing body of evidence suggested that subjects with unipolar major depression had significantly elevated concentrations of glutamate compared to age-and-sex-matched healthy controls.3 Thus, it was hypothesized that an imbalance in glutamatergic neurotransmission may contribute to increased concentrations of NMDA agonism, in brain circuits involved in major depression. In 2006, Zarate et al, conducted a double-blind trial and concluded that ketamine, a selective and potent NMDA receptor antagonist, given as a single dose, exerts rapid antidepressant effects in a treatment refractory population.2,3
Ketamine, classified as a dissociative anesthetic, hallucinogen and a psychomimetic, is structurally similar to phencyclidine, a well-known recreational drug, but 10–50 times less potent at the NMDA receptor. It is used as a short-acting general anesthetic in humans, as a tranquilizer in animals and abused as a recreational drug.1 Ketamine for use in general anesthesia in humans was first approved by the Food and Drug Administration (FDA) in 1970. Its sub-anesthetic dose of 0.5 mg/kg administered via IV infusion for the purpose of treatment resistant depression is currently used strictly off-label.4
Psychologically, ketamine produces a dream-like state, decreased awareness of the environment with pseudo-hallucinations, out-of-body experiences and impaired thought processes. Physiologically, it may produce tachycardia, increased blood pressure, insensitivity to pain, amnesia, paranoia and schizophrenia-like symptoms. With long-term exposure, high tolerance, drug craving, and flashbacks have been reported. There is, however, little evidence of a physiologic withdrawal syndrome except in the case of abrupt discontinuation in chronic users of ketamine.1
A recent systematic review performed using all available published data on the antidepressant effects of ketamine reported that in most studies the administration usually involved an anesthesiologist injecting a single, sub-anesthetic dose of 0.5 mg/kg via IV infusion over 40–60 minutes which requires hospitalization for at least 24 hours post-infusion. The total number of ketamine administrations has varied from 1 to 3 (ad hoc) or 6 (planned). The authors defined the response to ketamine's antidepressant effects as 50% or greater reduction on at least one of the following depression measures: Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptoms (QIDS). Response rates ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion. Adverse effects were reported to be mild, with some patients experiencing brief changes in blood pressure, heart rate and respiratory rate. Authors, however, did not recommend ketamine administration outside of the hospital setting.5
An open label study found that six repeated ketamine infusions administered daily on days 1, 3, 5, 8, and 10 over the course of 2 weeks were safe and generally well tolerated in a group of 10 patients with TRD. At each infusion, ketamine diluted in saline to 0.5 mg/kg was administered over 40 minutes by an IV pump followed by a 4-hour continuous vital-sign monitoring period. The primary efficacy measure was a ≥ 50% reduction in the MADRS score from the pre-ketamine baseline. After the sixth infusion, nine patients responded with an 85% (mean) reduction in the MADRS score. Eight of those nine patients relapsed, on average, 19 days after the 6th infusion. Only one patient remained well for more than 3 months.2
A recent two-site, parallel-arm, randomized controlled trial compared a single infusion of ketamine to the anesthetic midazolam in patients with treatment-resistant major depression experiencing a major depressive episode. The study, which the researchers noted was the largest to date to test the antidepressant effects of ketamine, included 73 subjects who were randomly assigned in a 2:1 ratio to receive a single intravenous infusion of ketamine 0.5 mg/kg (N=47) or midazolam 0.045 mg/kg (N=25) infused over 40 minutes. The primary outcome was a change in depression severity 24 hours after drug administration, as assessed by the MADRS. The study showed the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71) and the likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. However, the depression scores were not significantly different between treatment groups at 7 days. The investigators noted that more research is needed to identify strategies needed to prolong the antidepressant effect of ketamine and to determine its safety profile before implementation in clinical practice.6
In the above trial, side effects associated with ketamine infusion included dissociative symptoms soon after administration in 8 patients (17%) and resolving 2 hours post-infusion. In addition, ketamine infusion was terminated in one patient due to a blood pressure elevation (peak, 187/91 mmHg) and in another due to transient but pronounced hypotension and bradycardia.6 Overall, in the clinical literature, primary complications of subanesthetic doses of ketamine are considered manageable and have included brief hypertensive episodes, transient tachycardia, premature ventricular contractions, bradycardia, hypotension, bradypnea, dry mouth, blurred vision, headache, and reduced oxygen saturation.4
In addition to antidepressant effects, clinical observations from several pooled studies show that ketamine has robust anxiolytic effects, anti-suicidal effects, and does not appear to change Young Mania Rating Scale and Brief Psychiatric Rating Scale scores in major depressive disorder and bipolar depression.1 In clinical trials, patient exclusion criteria often consisted of the following: less than 18 or greater than 65 years, past history of psychotic symptoms or mania, substance use disorders (<3 months before screening), current active suicidal ideation judged to cause an immediate danger, abnormal electrocardiogram, any unstable medical illness or laboratory tests, uncorrected hyper- or hypothyroidism, pregnancy or initiation of hormonal treatments (<3 months before screening), use of psychotropic medications for <2 weeks (4 weeks with fluoxetine) before first infusion, and previous treatment with ketamine.4 Since most studies were done under controlled conditions, it is difficult to identify the population who should not get ketamine at this point in time. Furthermore, the inclusion and exclusion criteria were quite selective and, therefore, generalizability of the results is limited.
Most clinical trials have used a dose of 0.5 mg/kg administered via IV infusion over 40–60 minutes. It is reported that generally if an antidepressant response is to occur, it will be observed within 2–6 hours. Subjects were monitored for a minimum of 4 hours with some remaining overnight for prudent assessment of vital signs. Administration of multiple ketamine infusions (e.g., 3 times a week for 2 weeks) was studied less frequently and with a small number of subjects.4
In comparison to ECT, there are no published head-to-head studies. However, it is stated that application of ketamine infusions could be made available to a larger population of treatment-resistant cases than ECT because less specialty equipment is required. In clinical trials, treatment resistant patients have returned to antidepressant medications following ketamine treatment and an estimated 25–33% previously treatment-resistant patients have become responsive to combinations of antidepressant treatment following ketamine.4
There are several phase 2 trials in the pipeline to develop ketamine-like drugs devoid of dissociative, psychomimetic or euphoric side effects says Carlos Zarate, of the National Institute of Mental Health, a leader in researching ketamine for depression (Table 1).1
BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF)
The loss of BDNF is another change found in subjects with major depression. BDNF is a member of the nerve growth factor family, which helps with the survival and growth of neurons. However, stress seems to decrease levels of BDNF and increasing BDNF may be a new target for antidepressant action.14 Patients who did not respond to ketamine were carriers of Val66Met (rs6265) single-nucleotide polymorphism (SNP) which is associated with an attenuation of brain-derived neurotrophic factor (BDNF) functioning.15 It is postulated that the BDNF gene Val66Met polymorphism influences the response to ketamine, suggesting that a surge of BDNF following NMDA receptor blockade is likewise necessary to induce antidepressant-like effects.1
FOCAL BRAIN STIMULATION
The emergence of brain stimulation therapies over the past few decades has been facilitated by neuroimaging studies that have helped to map out a network of brain regions involved in depression, which may serve as targets for direct neuromodulation.2 Two of these procedures, vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS), are currently approved by the FDA and have been recently reviewed by Crouse,16 and hence they will not be reviewed here.
DEEP BRAIN STIMULATION (DBS)
DBS, yet to be approved by the FDA, is a reversible, invasive technique done under anesthesia and involves implantation of electrodes powered by a pulse generator into the specific dysfunctional region of the brain. In one study, ten patients with severe TRD were implanted with bilateral DBS electrodes and twelve months later five patients reached 50% reduction of the HDRS score, with significant increases in pleasurable activities. In another study of 21 patients it was found that patients treated with DBS had variable response with time: 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS increased to 62% when the response was redefined as a reduction in the baseline HDRS of 40% or more. On a long term basis (<6yrs), DBS was shown to be safe and effective in patients with TRD and well tolerated with minor hemorrhagic events. Table 2 lists positive and adverse effects of DBS.17
TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS)
A noninvasive technique with no FDA approval, tDCS modulates cortical excitatory tone via a weak electrical current generated by two scalp electrodes. In 3 sham-controlled randomized trials, 5 to 10 treatment sessions of tDCS given during a 2 week period has been compared to placebo stimulation and as an add-on to an antidepressant medication with mixed results. Two of the studies were positive in significantly improving depression scores (measured using HDRS and BDI) and addressed the usefulness of tDCS. However, overall, authors have concluded that more controlled trials evaluating the efficacy over a longer period are needed in patients with TRD.17,2
MAGNETIC SEIZURE THERAPY (MST)
MST, also known as magnetic convulsion therapy and yet to be approved by the FDA, use magnetic fields to induce seizures. Small pilot studies conducted suggest MST and ECT have comparable efficacy and that the cognitive side effect profile of MST is better than ECT as it is a more focal administration. Notably postictal orientation recovery time is short and rapid with MST and it is reported to result in minimal retrograde and anterograde amnesia. A twenty-patient open label study randomly assigned patients to receive either MST or ECT as add-on therapy to controlled pharmacotherapy for more than 2 years, showed a 50% improvement in MADRS ratings in both treatment groups. Investigators suggested that MST may be a potential alternative to ECT if efficacy and safety are validated in larger clinical trials.17 Similar to ECT, MST is performed under general anesthesia and involves a serial induction of seizures over several weeks.2
Progress to date with brain stimulation techniques has been limited. FDA approved stimulation therapies are associated with relatively low response and remission rates and neither has shown efficacy in extreme cases of TRD. Data on the remaining brain stimulation techniques are too preliminary to draw meaningful conclusions in their efficacy or safety.2
While substantial information is lacking to develop a recommendation for practice guidelines in TRD, current small-scale studies have provided some clinical evidence for the use of ketamine and ketamine-like treatments in a selective group of patients with TRD; however, optimal dosing and treatment length have yet to be determined. Review of literature on the role of neuromodulation methods indicates promising therapies. Further well-designed studies that recruit a larger and a more diverse group of participants with TRD will strengthen the evidence and offer more clarity about treatment options.
The author discloses no conflicts of interest in this manuscript.