Novel Approaches to Treatment-Resistant Depression

Everyone experiences feelings of sadness from time to time. Clinical depression, however, is a more serious state of low mood that affects all aspects of everyday life from the ordinary and routine like eating and sleeping to the more complex such as work, school, and relationships. Clinical or major depression is one of the most common mental illnesses. Yet, despite its high prevalence, depression remains significantly underdiagnosed and untreated. It is estimated that only about 30% to 40% of people in the community who meet diagnostic criteria for depression receive any form of medical or psychological treatment.

Affective disorders, also called mood disorders, include two conditions: major depressive disorder and bipolar disorder. Depression is the most prominent feature of bipolar illness as well.

Of concern are the significant personal and social consequences of depression on affected individuals and their families. Depressed persons often perform poorly in marriage and relationships with family members. They may respond negatively to others as well which can precipitate stressful life events that exacerbate depressive symptoms. Although most people who are depressed do not kill themselves, untreated depression increases the risk of suicide. It is not uncommon for depressed individuals to have thoughts of suicide, whether or not they intend to act on these thoughts. Severely depressed people often do not have the energy to harm themselves; but if and when their depression does remit, even partially, they are then able to access the energy needed to act on these thoughts.

First-Line Treatment for Depression

Although other treatment modalities are available, antidepressant pharmacotherapy remains the mainstay of treatment. A wide range of classes of antidepressant drugs exists from which to choose. Antidepressants primarily work by elevating levels of the three key neurotransmitters in the brain: serotonin, norepinephrine, and dopamine.

Selective serotonin reuptake inhibitors (SSRIs—fluoxetine, paroxetine, sertraline, citalopram, and escitalopram) increase serotonin levels.

Serotonin noradrenaline reuptake inhibitors (SNRIs—venlafaxine and duloxetine) increase the levels of both serotonin and noradrenaline. However, the neglected neurotransmitter in this equation is dopamine, because the most widely used antidepressants that block reuptake of biogenic amines do not block dopamine transporters.

Dopamine has been linked to lack of motivation and anhedonia, or lack of interest in previously pleasurable activities. Triple reuptake inhibitors (TRIs) have been in development for at least the past decade. Hypothetically, this type of drug would produce a more rapid onset and better efficacy (higher response and remission rates) than current antidepressants in part due to the addition of the dopamine component. In addition, it is possible that some of the sexual dysfunction related to serotonin transport blockade, seen very commonly with SSRIs, would be attenuated or even eliminated due to the addition of the dopamine component. 

When First-Line Treatments Do Not Work

Despite the widespread availability of effective treatments for depression, many patients do not receive adequate relief from symptoms. A large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness study showed that approximately half of patients will respond to an initial trial of an antidepressant, with only a third reaching clinical remission with that first trial. Moreover, up to a third of patients may not reach remission despite multiple drug trials. These response and remission rates highlight the fact that there is no broad consensus as to what defines treatment-resistant depression (TRD). In some clinical trials, TRD is defined as a failure of one previous antidepressant regimen during the current treatment episode, while in other studies TRD has been defined as at least four antidepressant failures with or without failure of electroconvulsive therapy (ECT).  It is most useful to conceptualise TRD as existing on a spectrum, from failure to respond to one standard antidepressant trial, to failure of multiple antidepressant classes or augmentation strategies, to failure of ECT.

Managing Treatment-Resistant Depression

There are several approaches to the pharmacotherapy of TRD, starting with optimisation of the current treatment. If this fails, more significant changes are undertaken, such as switching within or between classes of medications, or augmenting the primary antidepressant with another drug.

Optimisation

Optimisation involves ensuring that the current medication is being used for sufficient duration, at the ideal dosage, and with maximal adherence to treatment. A sufficient primary antidepressant trial duration is usually 6–8 weeks, although a small proportion of patients require as long as 12 weeks to respond.

Switching

If optimisation fails, one option is switching medications. Switches to an entirely different agent can be either within or between antidepressant classes. Within-class switches (e.g. SSRI to SSRI) are most commonly performed, exploiting the advantage that there is significant cross-tolerability between different drugs within the same class, so that such switches can be performed relatively quickly. Previous reviews have suggested comparable response rates for within- and between-class switches. Switching to a different class (e.g. from an SSRI to bupropion or SNRI) is another option, and at least one meta-analysis has identified a significant, albeit modest, advantage in switching from SSRIs to non-SSRI treatments. Another between-class switch option involves switching to an older drug, such as a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI). Both of these classes have limitations, notably anticholinergic and cardiovascular side effects with the TCAs, and dietary and drug interactions with the MAOIs.

Augmentation

Another major strategy in managing TRD is augmentation, the addition of a different medication, in a different class or acting via a different mechanism of action, to improve the antidepressant effects of an ongoing treatment. Augmentation using an antidepressant with established efficacy can also be referred to as combination therapy.

Lithium: Lithium augmentation is one of the oldest and most established of the augmentation strategies. In a meta-analysis of the 10 placebo-controlled studies examining lithium augmentation, lithium was substantially more effective than placebo. However, it is important to note that the database for lithium augmentation is older and was developed before most of the modern antidepressant drugs were available; the majority of the relevant studies were conducted when TCAs were the standard of antidepressant care, and the amount of evidence available for lithium as an augmenting agent for SSRIs is considerably less.

The only placebo-controlled lithium augmentation trial to retrospectively and prospectively establish treatment resistance failed to find lithium effective. In that particular study, 92 subjects with treatment resistant depression (defined by at least one, but no more than five, adequate trials of antidepressants) were treated with nortriptyline for 6 weeks. Those subjects who tolerated nortriptyline for 6 weeks and whose depression did not respond were randomised to receive either lithium or placebo augmentation of nortriptyline for an additional 6 weeks. After 6 weeks of double-blind augmentation, 12.5 % of subjects responded to lithium and 20.0% to placebo.

Thyroid hormone: Thyroid hormone supplementation (usually triiodothyronine [T3], but occasionally thyroxine [T4]) is another older and commonly used augmentation strategy. Its advantage is that it generally tends to be well tolerated and has a favorable side effect profile. The mechanism of action is unclear. Similar to lithium augmentation, much of the data supporting thyroid augmentation comes from studies with TCAs. There are several open-label studies showing benefits for thyroid augmentation in TRD patients using SSRIs as a primary treatment, and one controlled study showing no difference between augmentation with T3, lithium, and T3 plus lithium in TRD patients. The STAR*D study compared T3 and lithium augmentation and found no significant difference in remission rates between the two, but did find T3 was better tolerated.

Bupropion: Bupropion is both a dopamine and norepinephrine reuptake inhibitor. According to one review of the literature, both controlled and open-label studies support the effectiveness of bupropion in reversing antidepressant-associated sexual dysfunction, whereas open trials suggest that combination treatment with bupropion and an SSRI or SNRI is effective in treating major depressive disorder in patients refractory to the SSRIs, SNRIs, or bupropion alone.

Mirtazapine: The use of mirtazapine as an augmenting agent for TRD is supported by small-scale open-label and placebo-controlled trials.

Atypical antipsychotics: Antipsychotic medications are generally divided into two categories: first generation (typical) and second generation (atypical). The main difference between the two types of antipsychotics is that the first generation drugs block dopamine and the second generation drugs block dopamine and also affect serotonin levels. 

Most first-generation antipsychotics block dopamine receptors without affecting other receptor systems at therapeutic doses, but have been associated with dysphoria and induction of depression due to unopposed dopamine blockade. On the other hand, the variable affinities for serotonergic, dopaminergic, and noradrenergic receptors and less exclusive or tight dopamine blockade make the atypical antipsychotics more promising candidates for the treatment of major depressive disorder. 

Second generation antipsychotics, including olanzapine, quetiapine extended release (XR) and aripiprazole, have clearly demonstrated efficacy as augmentation agents for major depressive disorder patients.

Adverse side-effects

While the efficacy of the atypical agents for adjunctive therapy in major depressive disorder appears fairly well established, there are other considerations. Antipsychotics can produce unwanted movement disorders commonly known as extrapyramidal symptoms. They include ‘akathisia’ (motor restlessness), ‘dystonia’ (continuous spasms and muscle contractions), ‘pseudo-parkinsonism’ (rigidity, slowness of movement and tremor), and ‘tardive dyskinesia’ (irregular jerky movements). Evidence suggests that some of the second generation drugs have milder movement-related side-effects than the first generation drugs. Both first- and second-generation antipsychotics can also cause weight gain to a greater or lesser degree in the majority of patients. The weight gain can be of sufficient severity as to cause obesity and metabolic syndrome. There also appears to be an association between certain atypical antipsychotics (i.e. clozapine, olanzapine, quetiapine) and abnormally high serum lipids (cholesterol and triglycerides). However, promising new research has documented the safety and efficacy of metformin, an oral medication commonly used to treat type II diabetes, in attenuating antipsychotic-induced weight gain and normalising glucose metabolism.

Psychostimulants and stimulant alternatives

Stimulants are among the oldest medications used in psychiatry. Stimulants were introduced to the US clinical market in 1932. In the 1940s, stimulants found popularity in the United States as diet pills. Awareness of the abuse potential of stimulants first emerged in post–World War II Japan, where the government had been selling stimulants to the public without prescriptions. The Japanese government consequently began limiting availability of stimulants; this was followed by a similar series of restrictions enforced by the US government in the 1960s. Almost since their initial synthesis and release, stimulants have frequently been used off-label clinically for antidepressant purposes, even though no systematic studies prior to the last two decades have provided evidence of their long-term efficacy or safety.

Amphetamines, methylphenidate

Amphetamines and methylphenidate are two different classes of compounds, both of which are psychostimulants. The primary action of psychostimulants is to increase dopamine levels in the brain—dopamine is a neurotransmitter associated with pleasure, movement, and attention.

There are various types of amphetamines including amphetamine salts, dextroamphetamine, levoamphetamine, and lisdexamfetamine.

Amphetamines increase levels of dopamine in the brain by:

1) stimulating the release of dopamine from nerve terminals,

2) inhibiting the reuptake (reabsorption) of dopamine from nerve terminals, and

3) inhibiting the breakdown of dopamine. In addition to increasing dopamine levels in the brain, amphetamines also increases norepinephrine and serotonin by similar mechanisms.

While amphetamines have three ways of increasing brain dopamine levels, methylphenidate has only one—it is strictly a dopamine reuptake inhibitor.

Lisdexamfetamine is a ‘prodrug’ meaning that it is inactive until it is ingested and converted to the active drug (dextroamphetamine) in the intestines and/or liver. The greatest improvement reported following treatment with psychostimulants is in motor activity, mood, and psychomotor activity. An improvement in memory and concentration may be observed, in some cases accompanied by euphoria. Their acute effects develop within less than a few hours and most are short-acting, lasting 4 to 6 hours. Data regarding efficacy and safety of classic stimulants as adjunctive treatment in bipolar depression remain sparse. The theoretical risk of a stimulant precipitating mania has led most clinicians and researchers to opt for more traditional approaches for treating the depressed bipolar disorder patient.

Modafinil, armodafinil

Modafinil and armodafinil are closely related drugs used to increase energy levels and improve focus and alertness. Studies indicate that these drugs may work in a manner similar to amphetamines and methylphenidate (i.e. by inhibiting dopamine reuptake) but, unlike amphetamines which act on widespread brain areas, modafinil and armodafinil have much more localised effects on the hypothalamic structures involved in the regulation of sleep, wakefulness, and circadian rhythms. Modafinil has been investigated as an augmenting agent in two large, placebo-controlled trials. Initial improvement in depressive symptoms seen with modafinil was not sustained, although apathy and fatigue remained significantly improved from baseline. A subsequent retrospective pooled analysis suggested that modafinil augmentation may improve depression in TRD patients with significant sleepiness and fatigue. However, in a recent study of 786 patients, armodafinil 150 mg significantly improved symptoms of major depressive episodes associated with bipolar I disorder versus placebo and was generally well tolerated.

Noradrenalie reuptake inhibitors

Drugs that selectively inhibit reuptake of norepinephrine (noradrenaline) include atomoxetine and reboxetine.

Atomoxetine: Atomoxetine is a noradrenaline reuptake inhibitor used clinically for similar indications as are stimulants (e.g. attention deficit hyperactivity disorder [ADHD]). Atomoxetine did not separate from placebo in patients with a partial response to sertraline treatment in a large-scale placebo-controlled trial.

Reboxetine: After the publication of individual trials and reviews demonstrating the efficacy of reboxetine as an antidepressant, independent scientists from the German Institute for Quality and Efficiency in Health Care discovered that 8 out of 13 significant trials were excluded and accused the manufacturer, Pfizer, of publication bias. An independent meta-analysis in 2011, published in the British Journal of Medicine, concluded that reboxetine is indistinguishable from placebo in the treatment of depression.

Dopaminergic agents

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in depression and especially in major depressive disorder (MDD). Dopamine agonists bromocriptine and pramipexole exert antidepressant efficacy in a randomised placebo-controlled study in patients with MDD. In addition, it is suggested that dopaminergic neurotransmission may be a final pathway common for many antidepressant treatments. Additional evidence that associates dopamine neurotransmission with depression is the high incidence of depression among patients diagnosed with Parkinson’s disease, a neurologic disease involving the degeneration mainly of dopamine-synthesising neurons. The incidence of depression in Parkinson’s disease is in the range 30% to 50% and prevalence in some surveys is >60%. Adjunct treatment with dopamine agonists, either pergolide or pramipexole, had significant antidepressant effects in Parkinson’s disease patients according to the Zung self-rating scores or HAM-D. Pramipexole showed greater effect with 61% of Parkinsonian depressed patients reaching the “recovered” points in HAM-D, as compared with only 27% of those on sertraline. Given that the dopaminergic system is involved in the pathogenesis of both depression and Parkinson’s disease, it is hypothesised that triple reuptake inhibitors might have improved efficacy in treating Parkinson’s disease depression, with less likelihood of aggravating tremors.

Triple Reuptake Inhibitors

Given the critical role of dopamine circuits in mediating some depressive symptoms, a triple reuptake inhibitor—a broad-spectrum drug combining blockade of dopamine, serotonin, and norepinephrine transporters—is an attractive strategy to treat depression.

Hypothetically, this type of drug would produce a more rapid onset and better efficacy (higher response and remission rates) than current antidepressants due in part to the addition of the dopamine component. In addition, it is possible that some of the sexual dysfunction related to serotonin transport blockade, seen very commonly with SSRIs, would be attenuated or even eliminated due to the addition of the dopamine component. In particular, hyperprolactinemia, which causes impotence in males, would be less likely to occur since dopamine opposes serotonin-promoted prolactin release.

 A concern with drugs that block dopamine transporters is their potential reinforcing effects and abuse liability. Thus, triple reuptake inhibitors will likely receive extra scrutiny by regulatory bodies regarding their abuse liability. If these hypotheses are proven correct, the therapeutic profile of triple reuptake inhibitors would offer clear advantages over currently available antidepressants. 

Ketamine

Ketamine is a commonly used anaesthetic medication in veterinary medicine. It also has a reputation for being a recreational drug. Recent data, however, suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades. Several studies demonstrate that ketamine reduces depression within six hours, with effects that are equal to or greater than the effects of six weeks of treatment with other antidepressant medications. Ketamine’s effects have been noted in people with treatment-resistant depression, and it appears that one of the earliest effects of the drug is a profound reduction in suicidal thoughts. Until now, the only medications thought to reduce suicide risk have been lithium and clozapine. Recently the Food and Drug Administration awarded breakthrough therapy designation for the development of intranasal ketamine for treating depression. This is the first time this special designation, usually reserved for drugs targeting an epidemic or a deadly form of cancer, has been awarded for the development of a medication for a mental disorder. “Ketamine clinics” are springing up and using the drug off-label to treat depression. This remarkable discovery awaits the results of further clinical investigation.

Non-Pharmacologic Treatments Effective for Treatment-Resistant Depression?

The management of TRD can involve the use of non-pharmacologic interventions such as the use of cognitive behavioral psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and transcranial magnetic stimulation. The following information is taken directly from the U.S. Agency for Health Care Research and Quality in regard to non-pharmacological interventions for TRD:

Cognitive Behavioral Therapy (CBT) or Interpersonal Psychotherapy (IPT)

Use of CBT began in the 1960s. It is a type of psychotherapy that aims to modify distorted, maladaptive, and depressogenic cognitions and related behavioral dysfunction. The therapist first introduces the patient to the cognitive model. Agendas, feedback, and psychoeducational procedures are used to structure sessions. To treat depressed patients with CBT, therapists emphasise negatively distorted thinking and deficits in learning and memory functioning.

Developed in the 1970s, IPT helps patients explore social and interpersonal issues that relate to depressive symptoms. Depressive symptoms identified are related to one of the four key problem areas: grief, disputes, transitions, and deficits. After selecting a focus area, later sessions help the patient develop strategies to deal with the problem. CBT and IPT do not have any risks or side effects associated with them. Patients need to have normal cognitive functioning to comprehend the therapist's questions. CBT and IPT are comparable psychotherapies for major depression and appear to be as effective as antidepressant medication treatment although CBT may be more effective in patients with severe depression.

Electroconvulsive Therapy

The primary current role for electroconvulsive therapy (ECT) in depression is for treatment resistance or intolerance. Because ECT was introduced prior to U.S. Food and Drug Administration (FDA) device regulation, it was not subjected to formal review and approval as a device. It has since been classified as a class III device, which means that “insufficient information exists to determine that general controls are sufficient to provide reasonable assurance of its safety and effectiveness.” The FDA is reconsidering how it classifies ECT.

Vagus Nerve Stimulation (VNS)

VNS involves surgically placed electrodes around the left vagus nerve. The VNS device consists of a round battery-powered generator that is implanted into the chest wall and attached to wires threaded along the vagus nerve. The therapy includes minor surgery, lasting approximately 30 to 60 minutes. Once implanted, the generator pulses the nerve for 30 seconds once every 5 minutes. The total duration of this intervention is generally 10 weeks, although the stimulation can be extended for longer intervals. VNS was first used in patients with epilepsy; it was also found simultaneously to improve mood. The FDA approved VNS for TRD in July 2005, with labeled indication for “adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. 

Repetitive Transcranial Magnetic Stimulation (rTMS)

rTMS involves magnetic focal stimulation through the scalp. The current elicited by the electromagnetic coil stimulates nerve cells in the region of the brain involved in mood regulation and depression. It can be administered in an office setting without the use of anesthesia. Patients may perceive it as less threatening than ECT. Patients having conductive, ferromagnetic, or other magnetic-sensitive metals in the head or within 30cm of the treatment coil should not undergo this procedure. Sessions are usually 40 minutes in length, administered daily (usually only weekdays) for 2 to 6 weeks. rTMS is usually considered a reasonable option for acute treatment of TRD, as opposed to VNS and pharmacotherapy, which are predominantly used as long-term treatments for TRD. The FDA first approved this device in October 2008. The FDA states that rTMS is indicated for the treatment of major depressive disorder in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode.

Possible side effects with rTMS include mild headaches, syncope, and transient hearing changes. Although rTMS does pose a risk of seizure, it reportedly does not have the cognitive risks of ECT. 

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