Current Research in Treatment-resistant Depression....

Current Research in Treatment-resistant Depression: When to Augment and When to Switch: Introduction and Switching Strategies for Treatment-resistant Depression

Authors and Disclosures

Introduction

The goal of antidepressant drug therapy should be the absence of significant depressive symptoms along with a complete recovery of social and vocational function, referred to as full remission.[1] With any first-choice antidepressant medication, about 50% to 70% of patients will have a significant treatment response (usually defined as a 50% or greater decrease in depressive symptoms). Of these treatment responders, however, only about one half to one third attain a full remission. Hence, a significant proportion of depressed patients are left with residual or persistent symptoms despite apparently adequate antidepressant therapy. Treatment-resistant depression (TRD) is therefore defined as the failure to achieve full remission with an antidepressant drug used at an adequate dose for an adequate duration of time.[2] When patients have not had a satisfactory response despite optimal treatment, the 2 basic treatment strategies are switching to an alternative antidepressant therapy or adding a second antidepressant therapy.[3,4] The failure to achieve remission with antidepressant therapy is associated with an increased risk for relapse or recurrence, higher levels of impaired social and vocational function, and a worse long-term prognosis. A significant minority of patients having chronic TRD (about 20% to 30%) do not have a satisfactory response to sequential trials of various drug-drug and drug-psychotherapy combinations.[1] Chronic TRD is associated with persistent social and vocational disability, an increased risk for suicide, greater medical morbidity and mortality, and higher healthcare utilization and costs.[5-7] In this article, I will review various treatment approaches for TRD, but will emphasize combination and augmentation strategies.

Switching Strategies for Treatment-resistant Depression

Switching to an alternative antidepressant drug is generally recommended for patients who have shown minimal or no response at all to the first antidepressant, or for those who have intolerable side effects, because adding a second medication is unlikely to be more effective or better tolerated than trying the second medication alone.[3]The serotonin reuptake inhibitor (SRI) drugs are the most commonly used class of antidepressants, and they are often the first-choice treatment. Although these drugs have a similar mechanism of action, individual patient response to different medications within the class of SRI drugs may vary considerably because these drugs are chemically dissimilar. Patients not responding to 1 SRI therefore may be appropriately switched to a second alternative SRI. Patients not responding after 2 adequate SRI trials, however, generally should be switched to an alternative antidepressant from another class. The older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are available, but are not commonly used because of their adverse side effect and safety profiles. These drugs can be effective for TRD, however.[8,9] A transdermal formulation of the MAOI selegiline, which is safer and better tolerated than older MAOI drugs, may be a more popular MAOI treatment option for TRD, although it has not been formally studied in these types of patients.[10

^{Combination and Augmentation Strategies for Treatment-resistant Depression}

Combination therapy typically refers to the combined use of 2 US Food and Drug Administration (FDA)-approved antidepressant drugs, whereas augmentation refers to the addition of a second non-antidepressant agent to an antidepressant drug. Adding a second medication to the primary antidepressant drug may be most useful in patients who have shown at least a partial response to the antidepressant, because of the potential additive or synergistic effects.[11] Combining different medications should also be considered for patients who have not responded to multiple monotherapy trials using antidepressants from several different classes. Although the response to combination or augmentation may sometimes occur rapidly at an initial dose of the second medication, it is still important to optimize the dose and duration of each treatment when they are used together.

Combining Antidepressant Drugs

With the exception of MAOI drugs, combining 2 or more antidepressant drugs usually can be safely done. Combinations with TCAs and other antidepressants have been described in the literature, but virtually all reports are based on uncontrolled studies. The effectiveness of various antidepressant combinations for TRD has not been well studied or clearly established.[12] Combining an SRI drug with bupropion or mirtazapine is a common although not thoroughly investigated, strategy.

Combination with bupropion is a popular strategy, but its efficacy for TRD has not been systematically studied.[13]In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the efficacy and tolerability of various antidepressant therapies were evaluated through 4 sequential treatment steps.[14] In the medication augmentation arm of the second level of STAR*D, nonremitters to citalopram were randomized to receive augmentation with bupropion or buspirone.[15] The bupropion and buspirone groups had similar rates of remission and response. Bupropion, however, was associated with a significantly greater reduction in depression scores (from baseline to the end of level 2) than was buspirone, and it was associated with a significantly lower dropout rate due to intolerance than was buspirone.

Because of its unique pharmacology, mirtazapine combination is another approach. In a randomized controlled trial, patients who had failed to respond to at least 4 weeks of monotherapy with a newer generation antidepressant drug (an SRI, venlafaxine, or bupropion) continued to take the ineffective drug and were randomly assigned to receive four weeks of augmentation with either mirtazapine or placebo.[16] Response rates for mirtazapine augmentation (63.6%) were significantly better than those for placebo (20.0%). When 9 placebo nonresponders were treated openly with mirtazapine at the end of the study, 5 patients (55.5%) remitted. For the last level of STAR*D, nonremitters after the first 3 treatment steps were randomly assigned to switch to tranylcypromine or to venlafaxine/mirtazapine combination.[17] Remission rates were lower for tranylcypromine compared to venlafaxine/mirtazapine, although the difference was not statistically significant. Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance than was the combination.

Augmentation With Mood Stabilizer Drugs

Lithium is an FDA-approved mood stabilizer treatment for bipolar disorder. Based on randomized placebo-controlled studies, lithium is the most extensively studied and best established augmentation strategy for TRD.[18]It is not commonly used in contemporary clinical practice because of its perceived adverse side effects and safety.[19] When used, it is most effective at a dose that achieves a blood level of 0.8 mEq/L or greater.[20] In the augmentation arm of the third level of STAR*D, nonremitters after 2 treatment steps were randomly assigned to augmentation with lithium or thyroid hormone (triiodothyronine; T3).[21] Remission rates were lower for lithium compared to T3, but the difference was not statistically significant. Lithium was more frequently associated with side effects, and more patients taking lithium left treatment because of side effects.

Anticonvulsant drugs are FDA-approved for the treatment of seizure disorders. Many are commonly used as mood-stabilizing drugs for the treatment of bipolar disorder, and valproic acid, carbamazepine, and lamotrigine are FDA-approved for this indication. Anticonvulsants typically have relatively better antimanic effects than antidepressant effects, but lamotrigine is somewhat unusual in having relatively better antidepressant effects.[22] Lamotrigine decreases the release of the excitatory amino acid glutamate, and it also has modest blocking effects on the reuptake of serotonin and dopamine. Several open-label studies found it effective for unipolar TRD.[23,24] A small placebo-controlled study did not demonstrate significant benefit for lamotrigine augmentation in TRD on the primary outcome measure, but it was significantly more effective than placebo on several secondary outcome measures.[25] In an open-label randomized study, lamotrigine and lithium augmentation were similarly effective.[26]Carbamazepine has a main chemical structure similar to TCA drugs. It was found to have significant antidepressant effects in a unipolar treatment-naïve patient group.[27] In an open-label randomized study, carbamazepine and lithium augmentation were similarly effective for TRD.[28]

As a class, the pharmacology of second-generation (atypical) antipsychotic drugs (SGAs) is very complicated. Because of their dopamine-2 receptor blocking effects, SGAs are classified as antipsychotic drugs and are all FDA-approved for the treatment of schizophrenia. The SGAs have significantly greater effects on blocking serotonin-2 receptors compared to first-generation (typical) antipsychotic drugs (FGAs), and SGAs have effects on other neurotransmitters and their receptors.[29] These pharmacologic effects vary among each of the SGA drugs. The constellation of these pharmacologic properties has 2 important clinical implications. First, SGA drugs are generally less likely to be associated with Parkinsonian effects compared to FGA drugs. Second, many of the SGAs appear to have antidepressant effects. FGA and SGA drugs are effective for the acute treatment of mania. However, the additional antidepressant effect of SGA drugs contributes to their overall mood stabilizing qualities.

The investigation of SGA drugs to augment antidepressants for unipolar TRD in randomized placebo-controlled trials has increased considerably in recent years.[29] With the exception of lithium, these drugs are now the best studied augmentation agents for TRD. Aripiprazole is FDA-approved as an add-on therapy (together with another antidepressant drug) for TRD.[30] The proprietary combination of fluoxetine and olanzapine (olanzapine-fluoxetine combination) is FDA-approved for TRD.[31] Risperidone[29,32] and quetiapine[33,34] have also been shown to be effective for TRD, but are not FDA-approved for this indication. Ziprasidone has not been as well studied for TRD.[35,36]

Augmentation With Endocrine Hormone Drugs

The antidepressant use of thyroid hormone is based on the known association between depression and hypothyroidism, as well as on evidence that the hypothalamic-pituitary-thyroid axis is important for neuronal function and neurotransmission in the brain.[37] Thyroid augmentation has been studied almost exclusively in TCA nonresponders, and these studies have suggested that it may be more effective in women, perhaps because of their higher risk for thyroid disease.[38] Thyroid hormone augmentation has been less well studied than lithium or SGA augmentation, but better studied than other combination and augmentation strategies. T3 is easier to use and has been better studied than thyroxine. In a placebo-controlled comparison, T3 and lithium augmentation were similarly effective for TCA TRD.[39] However, as described above, T3 was somewhat more effective and better tolerated than lithium in the level 3 augmentation arm of STAR*D.[21]

Abnormal regulation of the hypothalamic-pituitary-adrenal axis, leading to persistent elevations in cortisol levels, has been implicated in the pathophysiology of depression.[40] A number of open-label and controlled studies of drugs that suppress or inhibit hypothalamic-pituitary-adrenal axis function, such as dexamethasone, aminoglutethimide, metyrapone, ketoconazole, and mifepristone, have shown some benefit for the treatment of major depression, including TRD.[41-47]

Several lines of evidence have suggested an important role for gonadal and adrenal steroid hormones in mood regulation. Women are especially vulnerable to mood disturbances during premenstrual, postpartum, and perimenopausal periods.[48] There also is evidence that mood disturbances may be associated with decreased steroid hormone levels in men.[49] In addition, steroid hormones act on specific receptors in the brain and affect neuronal function and neurotransmission. Considerable evidence suggests that estrogen may improve mild mood symptoms in perimenopausal women, but there is less consistent evidence that estrogen or estradiol are effective as monotherapy for clinical depressive syndromes.[50-52] There also is inconsistent evidence of the antidepressant effects of testosterone in men.[53,54] A small placebo-controlled study found that estrogen augmentation of antidepressants was effective for perimenopausal women with TRD.[50] Several placebo-controlled studies of testosterone augmentation in men with TRD had mixed results, although the sample sizes of the studies were small.[55] The adrenal steroid hormone dehydroepiandrosterone, which is precursor to testosterone and estrogen, has a significant role in mood regulation.[56] A small placebo-controlled study suggested benefit with dehydroepiandrosterone augmentation for TRD.[57]

Augmentation With Miscellaneous Drugs

Buspirone is a nonbenzodiazepine drug indicated for the treatment of generalized anxiety disorder. It is a partial agonist at post-synaptic serotonin-1A type receptors, modulating serotonin release, and has antidepressant properties at higher doses (eg, up to 60-90 mg/day). Some controlled studies have found buspirone augmentation to be effective in TRD.[58,59]

As described above, buspirone was somewhat less effective and less well tolerated compared to bupropion in the augmentation arm of the second level of STAR*D.[15]

Atomoxetine is a selective norepinephrine reuptake inhibitor antidepressant drug. It has relatively weak antidepressant effects, but is FDA-approved for the treatment of attention-deficit/hyperactivity disorder. A placebo-controlled study of atomoxetine augmentation for TRD found no benefit,[60] although the drug might be useful for treating fatigue associated with depression.[61]

Modafinil has a stimulating effect in the central nervous system, possibly by activating α-adrenergic and dopamine activity in discrete regions of the brain, but the effect is unlike that of methylphenidate or amphetamine. It is FDA-approved for the treatment of narcolepsy and excessive daytime sleepiness associated with sleep apnea. It is used as alternative treatment for attention-deficit/hyperactivity disorder, and is added to antidepressant drugs (typically SRIs) to augment their clinical effects and to treat certain adverse effects (eg, apathy, fatigue, and sexual dysfunction). A pooled analysis of 2 placebo-controlled augmentation studies found it modestly effective for improving depression, sleepiness, and fatigue.[62]

Pindolol is a β-adrenergic blocking drug with intrinsic sympathomimetic activity. Under conditions of increased adrenergic activity, it blocks postsynaptic β-1 and β-2 receptors. When basal levels of adrenergic activity are lower, however, it has weak partial agonist effects on these receptors. Pindolol also blocks presynaptic 5-HT1A receptors, an effect that increases the presynaptic release of serotonin from neurons. Based on these unique effects on adrenergic and serotonergic activity, pindolol has been used successfully to augment and accelerate the therapeutic effects of antidepressant drugs, although most controlled studies have not shown it to be very effective for TRD.[63]

Glutamate is the major excitatory neurotransmitter in the brain. Glutamate systems have been directly or indirectly implicated in mood disorders and other neuropsychiatric conditions. Glutamate receptor systems are very complex, and they can be segregated into various distinct receptor subtypes according to their molecular and pharmacologic properties.[64] The two main classes of glutamate receptors are referred to as "ionotropic" and "metabotropic." Ionotropic glutamate receptors are classified into 3 groups: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid , and kainate.

NMDA receptor antagonist drugs have antidepressant effects in animal models of depression. Ketamine, an anesthetic agent derived from the hallucinogenic drug phencyclidine, is a high-affinity NMDA receptor antagonist. In a double-blind crossover study of 18 patients with TRD, 2 doses of intravenous ketamine (at subanesthetic doses) or placebo were given 1 week apart.[65] Compared to placebo, ketamine was more rapidly and significantly effective in improving depressive symptoms. However, ketamine was also more likely to cause perceptual disturbances, confusion, and euphoria, which may be because it binds to an NMDA site that is closely associated with the phencyclidine binding site. Hence, the antidepressant usefulness of ketamine is limited due to potentially serious adverse effects, but this study confirms that NMDA antagonism has antidepressant effects.

The anticonvulsant lamotrigine, an approved treatment for bipolar disorder, decreases glutamate release. In a controlled study of nondepressed normal subjects given subanesthetic doses of ketamine, lamotrigine plus ketamine significantly decreased (compared to placebo plus ketamine) the perceptual disturbances associated with ketamine and significantly increased the immediate mood-elevating effects of ketamine.[66] However, a recent controlled study did not demonstrate that pretreatment with lamotrigine was more effective than placebo in attenuating the neuropsychiatric side effects of ketamine in patients with TRD.[67]

Riluzole is an approved treatment for amyotrophic lateral sclerosis. It inhibits the release of glutamate, but it also may have indirect effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptors and may increase the reuptake of glutamate. Several open-label studies have suggested that it may be effective and well tolerated in patients with TRD[68,69] and bipolar depression,[70] but no controlled studies have been reported. In a controlled study, riluzole was not significantly better than placebo for preventing relapse among a group of ketamine-responsive patients with TRD.[67]

Memantine is an approved treatment for Alzheimer's disease.[71] Compared to ketamine, memantine is a low-affinity NMDA receptor antagonist that is not associated with serious adverse neuropsychiatric effects.[72] A double-blind placebo-controlled study[73] of patients with major depression did not show that memantine was effective and it has not been studied in TRD.

In 1972, Janowsky and colleagues[74] hypothesized that the cholinergic system plays a central role in the pathogenesis of mood disorders. In a recent investigation of the potential antidepressant effects of the anticholinergic drug scopolamine, Furey and Drevets[75] reported on the results of 2 studies: an initial double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Among the 18 depressed outpatients, 12 were chronically depressed and 5 had TRD. Significant reductions in depression and anxiety ratings were observed after the administration of scopolamine compared to their baseline and compared with placebo. These scopolamine effects persisted when subjects switched to the placebo sessions. Patients acutely experienced elevations in confusion during scopolamine administration, but it was otherwise well tolerated.

Psychotherapy for Treatment-resistant Depression

Various short-term structured forms of psychotherapy have been developed specifically for treating depression.[76]These depression-focused psychotherapies include intensive short-term dynamic psychotherapy , interpersonal psychotherapy, various behavioral therapies, and cognitive behavioral therapy (CBT). Cognitive behavioral analysis system of psychotherapy is a modified form of CBT that incorporates some principles of interpersonal psychotherapy. Although combining pharmacotherapy and psychotherapy is commonly recommended in clinical practice, there is no clear evidence that the combination is more effective than either modality alone in the treatment of uncomplicated depressions. Combining psychotherapy and pharmacotherapy is more beneficial for treating and managing complicated depressions, such as chronic depression or TRD.[77,78] A number of reports have described the use of short-term dynamic psychotherapy,[79] interpersonal psychotherapy,[80] CBT,[81-83]behavioral therapy,[84] and cognitive behavioral analysis system of psychotherapy[85] for TRD.

In the second level of STAR*D, CBT was compared with medication augmentation and switch strategies for nonremitters to citalopram.[87] Patients were randomly assigned to augmentation (citalopram with CBT or with medication) or to switch (to CBT or to another antidepressant). Patients who received CBT (either alone or in combination with citalopram) had similar response and remission rates compared with those assigned to medication-only strategies. For patients who continued on citalopram, medication augmentation resulted in significantly more rapid remission than augmentation with CBT. Among those who discontinued citalopram (switching to CBT or to medication), there were no significant differences in outcome, although patients who switched to a different antidepressant reported significantly more side effects than patients who received CBT alone.

Neurostimulation Therapies

The oldest and most commonly known form of neurostimulation is electroconvulsive therapy (ECT). It has been shown to be highly effective for the treatment of TRD.[87] ECT involves the passage of a brief electrical current through the brain to induce a generalized seizure lasting about 30 to 90 seconds. A typical course of ECT consists of 6 to 12 treatments given 3 times weekly, although patients with TRD might require a greater number of treatments. One of 2 electrode placements is used for ECT: unilateral nondominant hemisphere placement or bilateral placement. Most patients are treated initially with unilateral ECT. Bilateral ECT usually is reserved for patients who have shown a minimal response after 6 unilateral treatments, or for patients with a history of a poor response to prior courses of unilateral ECT, a history of a positive prior bilateral ECT response, or extremely severe symptoms. Adverse cognitive effects have limited the popularity and use of ECT. Increased efficacy and side effects of ECT are correlated with higher intensities of the electrical current, and efficacy and side effects are also greater with bilateral ECT. The acute clinical benefits of ECT are usually time-limited, and most patients should receive longer-term continuation treatment with pharmacotherapy or with ECT. However, patients who failed to respond to adequate trials of antidepressant medication prior to ECT have a higher risk of relapsing with pharmacotherapy after successful ECT and therefore should preferentially receive continuation treatment with ECT.[88]

Repetitive transcranial magnetic stimulation (rTMS) is a novel noninvasive method for causing focal nonelectrical stimulation of the brain.[89] Unlike ECT, rTMS is not intended to cause seizures. With rTMS, a high intensity electrical current is passed through an electromagnetic coil on the scalp. Rapidly turning the current on and off generates repetitive pulses of a magnetic field that can be focused on particular regions of the brain, depending on the therapeutic intent. Low frequency stimulation inhibits neuronal excitability, whereas high frequency stimulation is excitatory. Typically, 5 rTMS sessions are administered weekly for 4 to 6 weeks for the treatment of depression. Adverse cognitive effects of rTMS are uncommon. Many short-term placebo-controlled studies (using sham rTMS) have used high-frequency rTMS focused on the left dorsolateral prefrontal cortex because this area is hypofunctional in depression.[90] Low-frequency rTMS focused on the right prefrontal cortex also is effective,[91]although this approach is less well studied than high-frequency left dorsolateral prefrontal cortex stimulation. Controlled studies of rTMS have found it effective in major depression,[92] including TRD.[93] Based on the results of a large multicenter study,[94] the use of rTMS has been approved by the FDA for the treatment of depressed patients who have not responded to a single antidepressant drug trial. The effectiveness of rTMS for more refractory forms of depression may be relatively less compared to ECT.[93]

The FDA approved vagus nerve stimulation (VNS) for refractory epilepsy in 1997 and for chronic TRD in 2005. The vagus nerve (cranial nerve X) is a parasympathetic nerve composed of afferent (carrying sensory information from the viscera) and efferent (regulating parasympathetic autonomic function) fibers. VNS involves the surgical implantation of a pacemaker-like programmable pulse generator, which is connected to and intermittently stimulates the left cervical vagus nerve. Studies in epilepsy patients found that VNS had positive effects on mood symptoms, and brain imaging and neurochemical studies have shown that VNS activates various limbic regions and affects various neurotransmitters. This work led to interest in studying VNS in depression. An open-label pilot study using VNS in a group of 60 chronic and highly treatment-resistant patients with unipolar or bipolar depression reported a response rate of approximately 40%.[95] VNS was very safe and generally well tolerated, similar to its safety and side effect profile in epilepsy. During long-term follow-up of 59 patients from this study, 44% were responders (27% remitters) at 1 year and 42% were responders (22% remitters) at 2 years.[96]

A multicenter randomized double-blind controlled acute treatment study comparing active VNS (device turned on) to sham VNS (device turned off) in 235 patients with chronic TRD did not find a statistically significant difference in response rates after 12 weeks of treatment (15% response with active VNS vs 10% with sham VNS).[97] At the end of this acute study, all patients received active VNS (device turned on) and were followed in a long-term treatment study.[98] A similar cohort of patients (with chronic depression or TRD) who did not receive VNS were recruited and followed long-term as a naturalistic control group.[99] After 1 year of follow-up, the VNS patients were significantly more likely to be improved (27% response; 16% remission) compared to the treatment-as-usual group (13% response; 7% remission). This study demonstrated that the effectiveness of VNS is well tolerated, increases with time, and is usually maintained, which is contrary to usual experience with pharmacotherapy in chronic TRD.[7] The use of VNS is safe and compatible with any psychotropic drug and with ECT, but cannot be used together with rTMS because of the magnetic effects of rTMS.

Neuroanatomic and brain imaging studies have identified a cortical-limbic-thalamic-striatal neural circuit that is important for understanding depression and obsessive-compulsive disorder (OCD).[100,101] Within this circuit, certain brain regions are relatively overactive whereas other regions are underactive. During the 1940s and 1950s, patients with severe intractable psychiatric disorders were sometimes treated by frontal lobotomy, so-called because these surgical procedures resulted in destruction of the white matter tracts of the frontal lobes of the brain. Although some patients improved, many others suffered irreversible personality deterioration as well as surgical complications. With the advent of psychotropic drug treatments, the use of this controversial treatment declined. Because available therapies are not always effective for some patients, the development of modern stereotactic neurosurgical methods[102] has led to a renewed interest in neurosurgical interventions. These involve the selective ablation or lesioning of particular brain regions that can be effective for TRD[103,104] and treatment-resistant OCD. Neurosurgical ablative therapy procedures for TRD include (1) anterior cingulotomy, (2) anterior capsulotomy, (3) subcaudate tractotomy, and (4) limbic leucotomy. Stereotactic neurosurgical methods have also been used to implant electrodes in the brain. Electrical stimulation by these electrodes with pacemaker-like devices can be used to modulate brain function, by stimulating or inhibiting the activity of specific brain regions, without causing permanent or destructive lesions that cannot be reversed.

The most widely used neurosurgical form of therapeutic brain stimulation is deep brain stimulation (DBS).[105] This involves the placement of stimulation electrodes into deep subcortical regions of the brain. The particular electrode placement depends on the condition being treated. Currently, DBS (with electrode placement in various basal ganglia) is an FDA-approved treatment for essential tremor,[106] Parkinson's disease,[107] and treatment-resistant OCD.[108-110] At least 5 different brain regions have been identified as potential targets for DBS in TRD.[111] Recent investigational studies of DBS for TRD have focused on 2 different regions: subgenual anterior cingulate (Brodmann area 25; Cg25), and ventral capsule/ventral striatum (VC/VS).

In depression, Cg25 is relatively overactive.[112] Twenty patients with TRD were enrolled in a pilot study using Cg25 DBS.[113] On average, the patients had been in a current episode of depression for 6 years and had failed at least 4 different antidepressant treatments. Seventeen patients had received ECT previously. One month after surgery, 35% of patients met criteria for response and 10% met criteria for remission. Six months after surgery, 60% of patients were responders and 35% met criteria for remission. These benefits were largely maintained at 12 months. The number of serious adverse effects was small with no patient experiencing permanent deficits. Three subjects had the device removed because of infection, but 1 of these subjects later had the device re-implanted. One perioperative seizure occurred. Transient adverse mood changes were noted in several patients. There were no adverse cognitive effects.

Another research group has focused on VC/VS DBS in patients with TRD. This region is close to where DBS for treatment-resistant OCD has been targeted. Studies of DBS for treatment-resistant OCD found that comorbid depression often improved. The VC/VS region is relatively underactive in depression.[101] In an initial report of a pilot study using VC/VS DBS for TRD, 5 patients were implanted.[114] By 3 months, 3 patients were responders and 2 patients were partial responders. In a subsequent report of 15 patients from this study followed from 6 months up to 4 years, the 6-month response rate was 47% and the remission rate was 27%.[115] At the last follow-up visit (mean of 24 months), the response rate was 53% and the remission rate was 33%. The patients in this study had been in a current episode of depression for at least 2 years and had failed about 12 different antidepressant treatments. All patients had received ECT and psychotherapy previously. The surgical procedure and stimulation with DBS were relatively well tolerated in these patients. Transient adverse mood changes were reported, but there were no adverse cognitive effects, seizures, infections, or other serious adverse events.

Discussion

For patients not responding adequately to an initial antidepressant medication, the 2 main approaches are switching or augmentation. The advantages of switching antidepressants include (1) typically greater empirical support for the efficacy of alternative antidepressants compared to most augmentation strategies, (2) less risk for adverse drug-drug interactions, (3) better compliance associated with monotherapy, and (4) generally lower cost associated with monotherapy. Disadvantages of switching include (1) potential clinical worsening associated with discontinuing a partially effective antidepressant, (2) a delay in the time to a therapeutic response to the new medication, and (3) the loss of potentially beneficial additive or synergistic drug-drug interactions. Advantages of augmentation include (1) easy implementation, (2) avoiding clinical worsening associated with discontinuing a partially effective antidepressant, (3) potentially rapid treatment response, and (4) gaining possibly beneficial additive or synergistic effects by combining drugs with different mechanisms of action. Disadvantages of augmentation include (1) greater risk for adverse effects or toxicity, (2) increased cost, and (3) poor compliance associated with polypharmacy.

Given the availability of a wide variety of potentially effective therapies, how does one choose among these treatments? Patient preference is important to consider. Patients who strongly favor medication or psychotherapy should be offered treatment as such. The choice of medication will depend on such factors as patient preference, treatment history, family treatment history, clinical symptoms, and expected side effect profile. For TRD, whether to switch, combine, or augment medications should depend on the availability of comparative data on the relative efficacy, tolerability, and acceptability of the treatment options. In the STAR*D study,[120] an equipoise stratified randomized design was used, such that patients could accept or decline particular treatments (similar to clinical practice) as long as sufficient options were left that allowed a randomization between at least 2 different options. Most patients only agreed to have their medication either switched or augmented; relatively few patients agreed to do both. As a result, definitively comparing strategies involving augmentation with those involving a switch could not be done.

Among depressed patients, a significant minority do not have a satisfactory response to sequential trials of various drug-drug and drug-psychotherapy combinations. ECT often is considered the treatment of choice for these patients. However, ECT may not be efficacious, well tolerated, or acceptable, or it may be contraindicated. Novel alternative approaches for TRD include various types of alternative neurostimulation therapies and neurosurgical therapy procedures. Potential noninvasive neurostimulation therapies for TRD include rTMS, but it may have limited efficacy for patients with extensive treatment failure histories. Among the invasive neurostimulation therapies, VNS is often positioned as a treatment for ECT-intolerant or ECT-resistant depression. Other investigational invasive neurostimulation therapies include DBS. Neurosurgical ablative therapy procedures would then be considered as a treatment of last resort.