PSYCHIATRIC ANNALS December 2009
Shifting the Paradigm in Treatment-Resistant Depression: Assessing Barriers to Responses and Applying Adjunctive Therapies for Better Patient Results

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Introduction Factors Limiting Response to Antidepressant Medications Jan Fawcett, MD Pharmacologic Treatment for Patients with Partial Response Roger S. McIntyre, MD, FRCPC Biological Predictors of Antidepressant Response Madhukar Trivedi, MD Brain Stimulation Treatments for Depression Mark S. George, MD The Role of Psychotherapy in the Management of Treatment-Resistant Depression Michael E. Thase, MD

Introduction

Depression is among the most common conditions for which patients seek medical attention. Most clinicians are well aware of the profound impact of depression on quality of life for patients and their families, and of the many challenges that complicate the treatment of depression. Clinical studies have traditionally sought to demonstrate that antidepressant medications, adjunctive agents, psychotherapy, or neuromodulatory approaches (eg, electroconvulsive therapy) significantly improve depression by showing that treated patients exhibit lower average scores on depression rating scales or higher treatment response rates than untreated patients. In these studies, treatment response has often been defined as an improvement from baseline by some percentage. However, there has been a shift in thinking over the years toward the belief that the goal of treatment should be remission of symptoms, not simply improvement.

During the last few years, we have witnessed rapid growth in our understanding of treatment-resistant depression, and renewed efforts to treat to remission as often as possible. Many controlled trials have demonstrated the efficacy and safety of new switching or augmentation regimens, the role of psychotherapy, and new neuromodulatory approaches. However, this work has also shown how far we still have to go to meet our goal of treatment remission. One of the most striking findings of recent research has been that even when the most intensive treatment regimens are used by well-trained, experienced therapists, roughly one-third of patients still do not attain remission with the strategies that are available today.

This monograph provides an overview of strategies for treatment-resistant depression. The information presented here includes recent research on a diverse group of strategies to improve treatment outcomes, including monotherapy and combination medication approaches, adjunctive psychotherapy, and neuromodulatory therapies. I thank the panel for their discussions that contributed to the development of this monograph, from which readers can expect to gain knowledge that will be useful in their ongoing efforts to achieve remission for their patients with depression.

Jan Fawcett, MD
Course Chair

Factors Limiting Response to Antidepressant Medications

Jan Fawcett, MD

Many factors contribute to inadequate treatment response in patients with major depressive disorder (MDD), including poor adherence to treatment, comorbid conditions, inaccurate diagnosis, or limitations of patient assessment and follow-up. In addition, antidepressant medication may be ineffective or difficult to tolerate, or the duration of treatment may have been too short. Recognition of common barriers to antidepressant response is essential to attain the best possible treatment outcomes in patients with MDD.

Treatment Adherence

The term treatment adherence has been defined in many ways. It has been divided by some authors into 2 principal aspects: treatment compliance (regularly taking the medication as prescribed) and treatment persistence (continuing to take the medication over time). Treatment adherence in routine clinical practice is much lower than most clinicians realize. Many studies have found that approximately 20% to 50% of patients discontinue antidepressant medication within the first few months, and that the risk of premature discontinuation is higher in patients who have not been previously treated.^1,2 Most patients who discontinue treatment do so without consulting a physician.³ An examination of predictors of adherence following psychiatric hospitalization among patients in the Veterans Affairs (VA) healthcare system found that patients with poor adherence were more likely to be male, younger, nonwhite, and to have substance abuse disorders.⁴ Patients with post-traumatic stress disorder (PTSD) or other anxiety disorders were more likely to remain adherent to therapy. Some evidence suggests that antidepressant selection significantly affects treatment adherence. For example, a retrospective analysis of pharmacy claims data from 75 managed care plans compared adherence rates among patients who were treated with antidepressant medications that were classified as third-generation (ie, were introduced after 2002), second-generation (ie, serotonin or norepinephrine/dopamine reuptake inhibitors that were introduced before 2002), or first-generation (ie, tricyclic antidepressants and monoamine oxidase inhibitors).⁵ Adherence over a 6 month period was low for all 3 drug classes, but tended to be better for third-generation medications (33.6%) than for second-generation (29.3%) or first-generation (12.4%) medications. Although it can be difficult to assess adherence in routine clinical practice, it is essential to continually evaluate adherence to ensure that patients with MDD are using their medications as prescribed.

Comorbid Conditions

Many comorbid conditions have the potential to significantly limit the response to antidepressant medication. The impact of comorbidity on treatment outcomes was recently evaluated in an analysis of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which enrolled more than 2,800 outpatients with nonpsychotic MDD from 18 primary clinics and 23 psychiatry care clinics.⁶ Patients with comorbid anxiety or substance abuse had much greater severity and duration of depression, lower rates of remission, and higher rates of medication intolerance and discontinuation. A recent study of nearly 880,000 patients with MDD in the VA healthcare system found that the odds ratio (OR) for completed suicide was significantly higher for patients with comorbid panic disorder (OR 1.26; 95% CI, 1.04 to 1.53) or generalized anxiety disorder (OR 1.27; 95% CI, 1.09 to 1.47).⁷ In addition, suicide risk was significantly higher for patients who were prescribed anxiolytic medications (OR 1.71; 95% CI, 1.55 to 1.88), and was especially elevated for patients taking high doses of anxiolytic medications (OR 2.26; 95% CI, 1.98 to 2.57). Thus, the combination of depression with anxiety or substance abuse is an important significant predictor of inadequate treatment response. Recent research also suggests that patients with depression associated with comorbid personality disorders, particularly borderline personality disorder, are less likely than those without personality disorder to respond to antidepressant medications.⁸ Therefore, the possibility of a comorbid condition should be taken into consideration when patients are not responding to their antidepressant medications.

Inaccurate Diagnosis

Depressive symptoms may be caused by endocrine or neurologic diseases, by malignancy, and by a number of other medical conditions. It is especially important to consider an undiagnosed primary medical condition in patients who are not responding to antidepressant treatment. Undiagnosed or misdiagnosed bipolar disorder variants have been increasingly recognized as a cause of poor response in major depression. Several studies have suggested that patients who exhibit depression accompanied by hypomanic symptoms are at high risk of conversion to bipolar disorder, and often stop responding to antidepressant medication after an initial response to therapy.⁹ These patients often describe a long history of transitory responses to several antidepressant medications. Missed psychotic depression may also result in treatment resistance, as these patients often require combination treatment regimens that include antipsychotic medications.¹⁰ It is not unusual for high-functioning patients with psychotic depression to successfully conceal overtly psychotic symptoms for extended periods of time. Undiagnosed comorbid substance abuse may also contribute to poor treatment response, and also increases the likelihood of adverse drug reactions between substances of abuse and antidepressant medications. Thus, when a treatment-resistant depressed patient is encountered, it is also necessary to reconsider the original diagnosis and confirm that no aspects of the diagnosis were missed.

Limitations of Assessment and Follow-up

Patients with depression require continual support and encouragement during the first few weeks of treatment, when many patients begin to experience side effects of treatment but have not yet experienced improvement in mood. Continued follow-up is important to help patients to remain on therapy, and is especially important for patients with comorbid conditions such as substance abuse and anxiety disorders.^6,7,11,12

Choice of Antidepressant Medication

The choice of antidepressants is also an important issue. Two large studies have examined response rates for patients with depressive symptoms who were treated using a variety of monotherapy and combination treatment regimens.

In STAR*D, patients with MDD who did not attain remission with the selective serotonin reuptake inhibitor citalopram progressed through a series of randomized treatment steps in which they were either switched to another antidepressant, or other medications or psychosocial therapies were added to the regimen.¹¹ This study has demonstrated that it is difficult to achieve remission in patients with MDD and to maintain remission over time with all of the medications that are currently available. For the study population as a whole, approximately 56% of patients attained remission after 2 steps. Of patients who progressed through 4 treatment steps, only 67% attained remission.¹³ Thus, more than 30% of patients continued to experience significant depressive symptoms despite intensive, escalating antidepressant therapy. Overall, the drop-out rate approached 50% after 2 years of treatment. These investigators found that attaining complete remission of depression is especially important, as the relapse rate was much higher for patients who responded to therapy but did not attain a full remission than for those who attained remission (Table 1).¹¹

The second study, Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), has raised important questions about the effectiveness of antidepressants in bipolar depression. Many clinicians have assumed that antidepressants are as effective in bipolar depression as they are in unipolar depression, although with a possible increased risk of mood cycling. However, results of the STEP-BD study have suggested that antidepressants do not significantly improve depressed mood in these patients.^14,15 In this study, patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus antidepressant medication or a mood stabilizer plus placebo for 26 weeks. Durable improvement in depressive symptoms (defined as at least 8 consecutive weeks of euthymia) was noted for 23.5% of patients who received the adjunctive antidepressant vs 27.3% of patients who received a placebo (P = .40).¹⁵ These data underscore the importance of identifying patients whose depressive symptoms reflect unrecognized bipolar variants, who are likely to represent a large proportion of treatment-resistant patients with depression.

Summary and Conclusions

Additional research is needed to identify treatment strategies that will enable more patients with MDD to attain remission, including more effective use of existing antidepressant medications, more effective treatment switching and augmentation strategies, and the role of atypical antipsychotics and other new medications. Pharmacologic agents with new mechanisms of action may be required to attain significantly improved rates of response and remission than are available with current therapies. More clinical studies are also needed to define the effectiveness of nonpharmacologic approaches, including behavioral and cognitive treatments, exercise, and phototherapy.

References

1. Trivedi MH, Lin EH, Katon WJ. Consensus recommendations for improving adherence, self-management, and outcomes in patients with depression. CNS Spectr. 2007;12(8 Suppl 13):1-27.
2. Vanelli M, Coca-Perraillon M. Role of patient experience in antidepressant adherence: a retrospective data analysis. Clin Ther. 2008;30:1737-1745.
3. Sawada N, Uchida H, Suzuki T, et al. Persistence and compliance to antidepressant treatment in patients with depression: a chart review. BMC Psychiatry. 2009;9:38.
4. Zivin K, Ganoczy D, Pfeiffer PN, Miller EM, Valenstein M. Antidepressant Adherence After Psychiatric Hospitalization Among VA Patients with Depression. Adm Policy Ment Health. 2009 Jul 16. [Epub ahead of print]
5. Sheehan DV, Keene MS, Eaddy M, Krulewicz S, Kraus JE, Carpenter DJ. Differences in medication adherence and healthcare resource utilization patterns: older versus newer antidepressant agents in patients with depression and/or anxiety disorders. CNS Drugs. 2008;22:963-973.
6. Howland RH, Rush AJ, Wisniewski SR, et al. Concurrent anxiety and substance use disorders among outpatients with major depression: clinical features and effect on treatment outcome. Drug Alcohol Depend. 2009;99:248-260.
7. Pfeiffer PN, Ganoczy D, Ilgen M, Zivin K, Valenstein M. Comorbid anxiety as a suicide risk factor among depressed veterans. Depress Anxiety. 2009;26:752-757.
8. Mercer D, Douglass AB, Links PS. Meta-analyses of mood stabilizers, antidepressants and antipsychotics in the treatment of borderline personality disorder: effectiveness for depression and anger symptoms. J Pers Disord. 2009;23:156-174.
9. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164:1348-1355.
10. Schatzberg AF. New approaches to managing psychotic depression. J Clin Psychiatry. 2003;64(Suppl 1):19-23.
11. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs. 2009;23:627-647.
12. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342-351.
13. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
14. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
15. Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166:173-181.

Pharmacologic Treatment for Patients with Partial Response

Roger S. McIntyre, MD, FRCPC

Treatment response to antidepressant medication is usually defined as an improvement of symptoms of at least 50% from baseline. Over the last decade, a growing number of researchers and clinicians have argued that the goal of antidepressant therapy should be complete remission, rather than the partial improvement of symptoms. Remission (the full abatement of depressive symptoms) provides patients with the greatest probability of a sustained recovery from depression.

Response and Remission Rates in Major Depressive Disorder

Many patients with depression do not attain response or remission with current treatments. In a recent meta-analysis of data from 93 clinical trials of patients with major depressive disorder (MDD), the treatment response rate to antidepressant medication was approximately 60%–65%.¹ There was a small difference between response rates for patients treated with selective serotonin reuptake inhibitors (SSRIs) (59.3%) vs dual-acting serotonin and norepinephrine reuptake inhibitors (63.6%; P= .003), although the clinical implications of this finding are uncertain.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial examined treatment with up to 4 successive steps of antidepressant combination/switch therapies with a goal of attaining remission.² Only 36.8% of patients attained remission with the first treatment (citalopram), 30.6% of patients attained remission after step 2, 13.7% attained remission after step 3, and 13.0% after step 4. Another 33% of the patients never attained remission even after 4 steps of antidepressant therapy. These data suggest that most patients will not attain remission of depressive symptoms with a single-agent approach that is common in primary care, and that a substantial number of patients will not attain remission even with the most intensive antidepressant medication regimens that are currently available. These investigators also found that the probability of relapse increased as a function of the number of steps that were required to attain remission. Relapse was noted for 40.1% of patients who were treated to step 1, 55.3% after step 2, 64.6% after step 3, and 71.1% after step 4. The time between remission and relapse was also shorter for patients who required more steps to attain remission.

Treatment Strategies for Resistant Depression: Antidepressants, Lithium, and Thyroid Hormone 

Controlled clinical trials have examined the effectiveness of a variety of add-on strategies, including combination antidepressant medication strategies, augmentation with an atypical antipsychotic, switching to another monotherapy, psychotherapy, and neuromodulatory approaches. Historically, most clinicians have been taught that patients who fail to respond to treatment with an SSRI should be switched to a non-SSRI therapy as the next strategy. In STAR*D, however, the remission rate for patients who were switched from citalopram to another SSRI (26.5%) was nearly identical to remission rates with the primarily noradrenergic agent bupropion sustained release (SR; 25.0%) or with the serotonin and norepinephrine reuptake blocker venlafaxine (25.0%).³

Some studies have suggested that treatment strategies that act at multiple neurotransmitter systems may result in higher response rates than treatments that focus on only one neurotransmitter system. Nelson and colleagues compared 3 treatment strategies for inpatients with nonpsychotic depression: desipramine plus placebo (N = 12), fluoxetine plus placebo (N = 14), or desipramine plus fluoxetine (N = 13).⁴ The remission rate after 6 weeks was much higher for patients in the desipramine plus fluoxetine group (54%) than the desipramine group (0%) or the fluoxetine group (7%; P = .001; Figure 1). In the STAR*D study, treatment options at step 2 for patients who did not attain remission with citalopram monotherapy included both monotherapy switch options (to venlafaxine SR, bupropion SR, or sertraline) and add-on antidepressant options (with bupropion SR or buspirone).^3,5 As noted previously, the 3 monotherapy switch strategies all produced remission in about 25% of patients at step 2. Remission rates were slightly higher for the add-on strategies (39% with citalopram and bupropion SR and 33% with citalopram and buspirone group). Augmentation with bupropion SR was associated with lower ratings of depression severity than augmentation with venlafaxine as assessed by secondary depression measures, and also had a lower rate of discontinuation due to intolerance.

The addition of mirtazapine to SSRI treatment is another common add-on strategy for patients who do not attain remission with an SSRI alone. In a randomized, double-blind clinical trial of 26 patients with MDD who had significant residual depression after treatment with an SSRI,⁶ mirtazapine produced a significantly higher response rate than placebo (64% vs 20%;P = .04) with a similar discontinuation rate (9.1% with mirtazapine, 13.5% with placebo). A more recent study compared mirtazapine (N = 21), paroxetine (N = 21), or the combination (N = 19) as an initial treatment strategy for patients with MDD.⁷ After 6 weeks, both monotherapy strategies improved the mean rating on the Montgomery-Åsberg Depression Rating Scale (MADRS) by approximately 10 points from baseline, compared with a mean improvement of more than 20 points with the combination. The combination therapy produced not only a greater average improvement in MADRS from baseline, but also a faster onset of antidepressant effect.

Augmentation with lithium or thyroid hormone [triiodothyronine (T3) in particular] has long been used to treat resistant depression. These agents have been used both as add-on therapies for partial responders and as accelerants to increase the rate of treatment response. Many clinical studies have demonstrated a rapid onset of mood improvement when lithium or T3 were combined with antidepressants for patients with partial treatment responses.^8,9 Most of these studies have examined lithium or T3 in combination with tricyclic antidepressants, although efficacy in combination with SSRIs has also been demonstrated. The STAR*D trial compared T3 and lithium in patients who did not attain remission after the first 2 treatment steps.¹⁰ Remission rates after an average of approximately 10 weeks were 15.9% for lithium augmentation and 24.7% with T3 augmentation (not statistically significant). Lithium was associated with a higher incidence of adverse events than T3, and was discontinued by significantly more patients (23.2% vs 9.6% with lithium and T3,respectively; P = .03).

Other Augmentation Strategies for Treatment-Resistant Depression

Atypical antipsychotics have been extensively evaluated for patients with treatment-resistant depression. A recent meta-analysis combined data from 16 randomized, placebo-controlled studies in which a total of 3480 patients with MDD were treated with SSRIs in combination with olanzapine, risperidone, quetiapine, or aripiprazole.¹¹ Each of the 4 atypical antipsychotics was significantly more effective than placebo, with odds ratios for treatment response that varied between 1.39 (with olanzapine) and 2.07 (with aripiprazole). Odds ratios for response did not differ significantly among the 4 atypical antipsychotics. Overall, remission was attained by 30.7% of patients who were treated with atypical antipsychotics vs 17.3% with placebo (P <.0001). Discontinuations due to adverse events were uncommon, but were more likely for patients treated with atypical antipsychotics than placebo (9.1% vs 2.3%; P <.0001). Quetiapine has also been examined as monotherapy in patients with depression, with response rates that are superior to placebo and similar to the antidepressant duloxetine.¹²

Some studies have suggested a possible link between depression and low dietary levels of omega-3 fatty acids.¹³ A recent meta-analysis of patients with MDD found that omega-3 fatty acid supplementation significantly improved depression in patients with clearly defined depression at baseline, with an effect size (difference between treated and placebo groups expressed in standard deviation units) of 0.69 (P = .002).¹³ There was no evidence of a dose-response effect among the studies included in the meta-analysis.

Finally, several antidepressant medications with novel mechanisms of action are currently being developed for the treatment of depression. For example, agomelatine is a new antidepressant that is currently approved in Europe but has not yet been approved in the United States. Agomelatine is a serotonin 5HT2c antagonist, and also acts as an agonist of melatonin M1 and M2 receptors, which are involved in the regulation of circadian rhythms. Response rates with agomelatine in clinical trials were approximately 50%–60%, which were superior to placebo and similar to paroxetine.^14–16

Summary and Conclusions

Most patients with MDD fail to achieve full remission with antidepressant medications despite the use of drug switches or add-on therapy. For those who do achieve remission, relapse is common. Improvement in treatment-resistant depression has been noted with the addition of other antidepressants to the treatment regimen, such as bupropion and mirtazapine. Beneficial effects have also been noted for patients treated with lithium, thyroid hormone, or atypical antipsychotics. Switching to another monotherapy remains an important alternative. Regardless of the particular strategy, it is essential to ensure that the patient is treated at an adequate medication dose and duration of therapy before concluding that the regimen is not effective. Taken together, the suboptimal remission rates with acute pharmacotherapy (monotherapy or combination) in the treatment of MDD provides the rationale for initiating combination treatment at the outset of therapy in a non-resistant patient. This strategy is under investigation at several centers throughout North America.

References

1. Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry. 2007;62:1217-1227.
2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
4. Nelson JC, Mazure CM, Jatlow PI, Bowers MB Jr, Price LH. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry. 2004;55:296-300.
5. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
6. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51:183-188.
7. Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine and paroxetine in major depression: a comparison of monotherapy versus their combination from treatment initiation. Eur Neuropsychopharmacol. 2009;19:457-465.
8. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53:842-848.
9. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
10. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519-1530.
11. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991.
12. Cutler AJ, Montgomery SA, Feifel D, Lazarus A, Aström M, Brecher M. Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study. J Clin Psychiatry. 2009;70:526-539.
13. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68:1056-1061.
14. Lôo H, Hale A, D'haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17:239-247.
15. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16:93-100.
16. Olié JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol. 2007;10:661-673.

Biological Predictors of Antidepressant Response

As described in detail elsewhere in this monograph, for the majority of patients with major depressive disorder (MDD), their illness does not respond adequately even with sequential treatments, including intensive medication augmentations/combinations or psychotherapy. Although the pathogenesis of depression is not completely understood, a large body of research over the last several decades has shown that the likelihood and severity of depression are influenced by an array of genetic, physiological, developmental, and environmental factors. Recent research has examined a number of potential physiologic or genetic predictors of treatment response among patients with depression. This research has identified several promising biologic markers that may eventually help to individualize antidepressant therapy.

Prefrontal Electroencephalogram Cordance

Prefrontal Electroencephalogram (EEG) changes have been observed to precede symptom improvement in patients receiving antidepressant medications for MDD, suggesting that EEG measures may provide a useful biomarker for treatment response.¹ Recent research has examined quantitative EEG (QEEG) cordance, which is a measure of brain electrical activity that correlates closely with regional brain perfusion. Studies of frontal theta QEEG activity have shown that decreased frontal cordance 2 to 7 days after beginning antidepressant therapy predicts the likelihood of treatment response several weeks later.^2–4 One recent study examined theta cordance changes in the midline and right frontal area (MRF) in 72 adult patients with depression who were randomized to treatment with antidepressant medication or placebo.¹ Remission was attained by 30% of patients with medication and 17% with placebo. MRF cordance at 1 week significantly predicted the eventual remission of depressive symptoms for patients in the antidepressant medication group with 69% overall accuracy (90% sensitivity, 60% specificity). Cordance was not associated with remission for patients in the placebo group.

Cytochrome p450 Genotyping

Individual patients often exhibit marked variability in their pharmacokinetic and pharmacodynamic responses to many different medications, including antidepressants.^5,6 Most antidepressant medications are extensively metabolized by hepatic cytochrome p450 enzymes (CYP450), especially CYP2D6. Polymorphisms of the genes encoding these enzymes may contribute to the variability in the pharmacological characteristics of antidepressant medications,⁷ and some research suggests that it may be possible to use information about a patient’s particular pattern of CYP450 gene expression to individualize antidepressant medication therapy. One recent study examined the interactions between age, sex, and CYP450 2D6 polymorphisms that are associated with extensive metabolism of selective serotonin reuptake inhibitors (SSRIs) in 71 patients who were being treated with paroxetine for depression.⁶ Mean plasma paroxetine concentrations were higher in women than men; they also tended to be higher for patients who were homozygous extensive metabolizers than heterozygous extensive metabolizers, although this difference was not statistically significant. The investigators noted that of the 2 patients who were considered poor metabolizers of paroxetine and 6 patients who were ultra rapid metabolizers, none responded to paroxetine therapy. A recent meta-analysis of 37 clinical studies, however, found only marginal association between CYP450 polymorphisms and the response to antidepressant therapy.⁸ One large study of older patients with depression found that poor CYP2D6 metabolizers were more likely to require a medication switch than extensive metabolizers if they were using tricyclic antidepressants, but not if they were treated with SSRIs.⁷ These studies suggest that cytochrome p450 genotyping may eventually play some role in the selection or modification of antidepressant therapy, but at present, there is not enough evidence to support genotyping in routine clinical practice. 

Gene Polymorphisms and SSRI Response

Polymorphisms of the serotonin transporter promoter region (5-HTTLPR) have recently been proposed as a potential marker of response to antidepressant therapy. The serotonin transporter (5-HTT) is a membrane protein that is located primarily on presynaptic membranes at serotonergic synapses. 5-HTT binds to and inactivates serotonin, and is important in modulating serotonergic activity within the central nervous system.⁹ Many clinical studies have examined the relationship between expression of 5-HTT protein and susceptibility to depression or response to treatment. In general, these studies have found that individuals with lower 5-HTT expression tend to be more susceptible to depression in response to environmental stressors, to respond less favorably to antidepressant medications, and are more likely to experience antidepressant-induced adverse effects.⁹ The SLC6A4 gene encodes the 5HTT protein and is located on chromosome 17. Two variants of the transporter promoter region have been identified in humans, which differ by a single 44-base-pair insertion (the long form, or L) or deletion (the short form, or S) of the SLC6A4 gene. The S form is associated with lower expression of HTT, and the presence of the S variant on one or both alleles of SLC6A4 has been linked to increased depressive symptoms in response to environmental stressors. A recent review examined the relationship between the low-expressing form of SLC6A4 and antidepressant treatment response in 13 clinical trials which together enrolled more than 3000 patients with depression (Table 1).⁹ As shown in the table, nearly all of these studies found either slower response rates or lower treatment response in individuals who were heterozygous (S/L) or homozygous (S/S) for the short form of SLC6A4, and greater response rates in individuals who were homozygous for the L variant (L/L). On the other hand, several studies in Asian populations have found higher rates of antidepressant response in patients with the S variant.⁹ However, the largest single study to examine the relationship between 5-HTTLPR polymorphisms and treatment outcome—the Sequenced Treatment Alternatives to Relieve Depression STAR*D study—did not find any significant associations between the S variant and treatment outcomes.¹⁰ These observations raise important questions about the true significance of the S variant in antidepressant treatment response.

Single Nucleotide Polymorphisms (SNPs) of many other genes have also been shown to correlate with treatment outcomes (response/remission and tolerability) of antidepressant medications, including genes that encode for neurotransmitter function, brain receptors for neurotrophic factors, potassium channels, proteins that make up the blood-brain barrier, and many others.^10–14 The identification of candidate genes has accelerated markedly during the last few years, especially with the increasing cost-effective use of rapid genome-wide association scans.¹⁴ Although many individual gene polymorphisms correlate only weakly with treatment response, it may eventually be possible to identify patterns of multiple alleles across many genes that, when analyzed together, prove useful for predicting treatment outcomes.¹⁵ However, presently the clinical significance of many of these genetic observations is not clear and at best accounts for only a small fraction of the clinical picture.

Summary and Conclusions

Several studies suggest that early changes in EEG cordance predict the eventual response to antidepressant treatment in patients with depression. The results of genetic studies have been more variable. Some research has suggested that it might be possible to use polymorphisms of CYP450 genes to predict antidepressant treatment responses, although several recent studies have reported only marginal relationships between CYP450 variants and treatment outcome. Polymorphisms of 5-HTTLPR have also been proposed as an important predictor of treatment response, yet the largest single study to examine this question found no relationship between 5-HTTLPR and treatment outcome in patients receiving SSRIs for depression. Many other gene polymorphisms have been linked to antidepressant response in individual studies, but the clinical significance of these findings is not clear at present. It may eventually be possible to use a detailed genome-wide profile to select an antidepressant treatment strategy for an individual patient. Eventually, composite markers that include behavioral (clinical/demographic and psychological) and biological markers (genetic, serological, and physiological) are very likely to provide a metric of the probability of response and tolerability to various antidepressant medications. A clinically relevant metric that individualizes treatment selection will transform the current trial and error process of selecting antidepressants to a more evidence-based process. 

Compiled by Mark P. Bowes, PhD
Reviewed by Madhukar Trivedi, MD

References

1. Cook IA, Hunter AM, Abrams M, Siegman B, Leuchter AF. Midline and right frontal brain function as a physiologic biomarker of remission in major depression. Psychiatry Res. 2009;174:152-157.
2. Cook IA, Leuchter AF, Morgan M, et al. Early changes in prefrontal activity characterize clinical responders to antidepressants. Neuropsychopharmacology. 2002;27:120-131.
3. Hunter AM, Leuchter AF, Morgan ML, Cook IA. Changes in brain function (quantitative EEG cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression. Am J Psychiatry. 2006;163:1426-1432.
4. Bares M, Brunovsky M, Kopecek M, et al. Early reduction in prefrontal theta QEEG cordance value predicts response to venlafaxine treatment in patients with resistant depressive disorder. Eur Psychiatry. 2008;23:350-355.
5. Lin KM, Perlis RH, Wan YJ. Pharmacogenomic strategy for individualizing antidepressant therapy. Dialogues Clin Neurosci. 2008;10:401-408.
6. Gex-Fabry M, Eap CB, Oneda B, et al. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit. 2008;30:474-482.
7. Bijl MJ, Visser LE, Hofman A, et al. Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol. 2008;65:558-564.
8. Thakur M, Grossman I, McCrory DC, et al. Review of evidence for genetic testing for CYP450 polymorphisms in management of patients with nonpsychotic depression with selective serotonin reuptake inhibitors. Genet Med. 2007;9:826-835.
9. Luddington NS, Mandadapu A, Husk M, El-Mallakh RS. Clinical implications of genetic variation in the serotonin transporter promoter region: a review. Prim Care Companion J Clin Psychiatry. 2009;11:93-102.
10. Kraft JB, Peters EJ, Slager SL, et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry. 2007;61:734-742.
11. Dong C, Wong ML, Licinio J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry. 2009;14:1105-1118.
12. Garriock HA, Kraft JB, Shyn SI, et al. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry. 2009 Oct 19. [Epub ahead of print]
13. Liou YJ, Chen TJ, Tsai SJ, Yu YW, Cheng CY, Hong CJ. Support for the involvement of the KCNK2 gene in major depressive disorder and response to antidepressant treatment. Pharmacogenet Genomics. 2009;19:735-741.
14. Schosser A, Kasper S. The role of pharmacogenetics in the treatment of depression and anxiety disorders. Int Clin Psychopharmacol. 2009;24:277-288.
15. Ising M, Lucae S, Binder EB, et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry. 2009;66:966-975.

Brain Stimulation Treatments for Depression

Mark S. George, MD

Over the last several decades, efforts to develop new therapies for depression have focused primarily on altering the synaptic activity of dopamine, serotonin, and other neurochemicals. However, it is important to recognize that the transmission of information within the central nervous system is an electrical process as well as a chemical one, and that the ultimate effect of antidepressant medication is to alter the flow of electrical currents within the brain. The brain is an electrical organ, and its currency is electricity. Recent research has suggested that a number of techniques to alter electrical activity in the brain are effective in the treatment of depression, and 3 of these techniques—electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and vagus nerve stimulation (VNS)—are approved by the FDA for the treatment of depression. Other brain stimulation techniques are in development but have not yet been extensively tested in patients with depression. Whereas pharmacological therapy exposes the entire body to a potentially therapeutic substance in order to treat a relatively small region of the brain, these neuromodulatory approaches are designed to target specific brain regions that are important in the pathogenesis of depression. They are not systemic and thus the side effect profile is different from medications, and there are minimal, if any, drug interactions.

Electroconvulsive Therapy

ECT was the first brain stimulation technique for the treatment of depression, and it remains the most effective acute treatment. Some studies have reported remission rates exceeding 70% in patients with severe major depressive disorder (MDD).^1,2 Although it was once generally believed that ECT effectiveness is linked to the induction of seizures, it has been recognized more recently that inducing a seizure is not sufficient to attain a significant antidepressant response, and that electrical stimulation must be applied to specific brain regions for antidepressant effectiveness. For example, the use of ECT to induce parietal lobe seizures is completely ineffective for the treatment of depression.³ In addition, more efficient techniques for delivery of electric current have been developed that are associated with a lower incidence of memory loss, which is a principal adverse event with ECT. In its early stages, ECT was administered using conventional alternating current with a sinusoidal waveform current distribution. It is now known that this approach is very inefficient because much of the current is delivered after nerve discharge has already occurred. There was an advance with brief pulse ECT, where the pulses are square and symmetric, but this variation was also inefficient. More recently, ECT has increasingly been administered using a procedure known as ultrabrief pulse ECT, which uses short-duration square-wave electrical pulses to produce electrical stimulation with less total current delivered to the brain.⁴

Treatment outcome in patients with MDD is significantly influenced by ECT parameters such as current path and current density. For example, one study examined treatment outcomes for patients with MDD who were randomized in a 2 x 2 factorial design to either high-dose or low-dose ECT, and to either unilateral or bilateral application.³ The response rate was much lower for patients with low-dose, unilateral ECT (17%) than with high-dose unilateral therapy (43%; P = .054), low-dose bilateral therapy (65%; P= .001), or high-dose bilateral therapy (63%; P= .001). More recently, Sackeim and colleagues have compared antidepressant efficacy and adverse memory effects for patients treated with a conventional brief ECT pulse (1.5 ms) or an ultrabrief pulse (0.3 ms).⁴ Patients were again randomized in a 2 x 2 factorial design to one of 4 treatment groups: unilateral vs bilateral application, and ultrabrief vs standard brief stimulation. In general, remission rates with right unilateral ultrabrief and standard ECT were similar; the response rate was lower with bilateral ultrabrief ECT. Ultrabrief administration was much less likely to produce retrograde amnesia for autobiographical information. As a result of findings such as these, unilateral ultrabrief ECT is becoming the standard of care for first-line treatment of patients requiring ECT.

Recent research has also examined the effectiveness and safety of combining ECT with pharmacotherapy in 319 patients with MDD.⁵ The conventional approach to ECT administration is to suspend antidepressant therapy, primarily due to concerns about safety. In this study, ECT combined with nortriptyline produced greater improvement than ECT combined with placebo on the HAM-D rating scale, with a lower incidence of adverse cognitive effects. Adjunctive venlafaxine was associated with less improvement in depressive symptoms than nortriptyline, and produced a higher incidence of cognitive adverse effects than nortriptyline or placebo. The results of this study suggest that it is possible to achieve greater reduction in depressive symptoms by adding ECT to antidepressant medication, but that medication selection is likely to be an important consideration in achieving the best possible outcomes.

Transcranial Magnetic Stimulation

In TMS, powerful electromagnets positioned near the skull create rapid magnetic pulses that generate a small electrical current within the superficial cerebral cortex.⁶ The efficacy and safety of TMS were demonstrated in a randomized, double-blind clinical trial of patients with unipolar, treatment-resistant MDD.⁷ Antidepressant medications were discontinued, and the patients were treated with either daily active TMS or sham TMS for up to 6 weeks. Daily TMS was associated with significant improvement in depression severity.

Although TMS is often combined with antidepressant medications in clinical practice, there is very little information about the efficacy and safety of TMS as an adjuvant. In addition, more research is required to understand how the effectiveness of TMS is influenced by treatment parameters such as the frequency of application, application site, or the intensity of magnetic stimulation. The available data suggest that TMS is associated with a low risk of adverse effects, and no interactions with pharmacotherapy have been identified. Approximately 20% of patients experience mild headache, which is usually relieved by acetaminophen. No detrimental cognitive effects have been identified; some studies have reported improved cognitive functioning after TMS treatment,⁸ which may reflect a beneficial cognitive effect of relieving depression. TMS has been available in the United States as an FDA-approved treatment for only one year, and the long-term effects of TMS treatment are unknown. Studies are just underway examining the durability of response after achieving remission, and whether and how to use TMS as a maintenance treatment.

Vagus Nerve Stimulation

In VNS, an implanted electrical stimulator is used to deliver mild electrical pulses to the left vagus nerve in the neck. The VNS unit is implanted in the chest wall during a simple surgical procedure, and is programmed to deliver electric current on a prespecified schedule (eg, 7 seconds of stimulation once every 2 minutes). Stimulation parameters may be easily reprogrammed during an office visit. The chronically implanted VNS device permits continuous long-term treatment of depression that is not limited by poor treatment adherence. VNS is FDA-approved for chronic, recurrent, treatment-resistant depression, and for patients with medically refractory epilepsy. The physiological mechanisms by which VNS improves depression and reduces seizures are not well understood.

The efficacy of VNS for depression has not been demonstrated in randomized, controlled clinical trials. One randomized study that was presented to the FDA for the approval of VNS did not detect a statistically significant difference between VNS-treated and untreated patients. A retrospective study that compared patients who had undergone VNS implantation vs treatment as usual in 329 patients with treatment-resistant MDD reported that VNS was associated with a 2-fold to 3-fold improvement in remission rate after 12 months (Table 1).⁹ The most common adverse effect is intermittent hoarseness of the voice during stimulation. VNS does not appear to cause cognitive adverse effects. In the absence of other long-term therapies for treatment-resistant depression, and considering the low risk of adverse events, the FDA approved VNS for treatment-resistant depression despite the lack of class 1 evidence; that is, without a randomized, controlled clinical trial demonstrating the acute or chronic efficacy of this procedure.

Deep Brain Stimulation

Deep brain stimulation (DBS) is a technique that could be potentially useful in the treatment of depression. But unlike the three techniques discussed above, DBS is still totally experimental and not FDA-approved. DBS involves drilling a hole into the skull, inserting a wire into the brain, and connecting the wire to a generator that is embedded in the chest wall that drives the deep brain stimulator. This technology has been shown to be successful in the treatment of Parkinson’s disease in nonresponsive patients through bilateral implantation in the subthalamic nucleus. It was also recently FDA-approved in a humanitarian device exemption for the treatment of obsessive compulsive disorder through implantation at the interior limb of the internal capsule. Its usefulness in the treatment of depression is still highly investigational. There are at least 3 different locations being investigated for the use of DBS in the treatment of depression (bilateral anterior limb of the internal capsule, bilateral cingulate gyrus, bilateral nucleus accumbens). There have been a total of <80 individuals worldwide implanted with this device for the treatment of depression, thus the data are minimal. There is, unfortunately, a 1% mortality rate associated with the implantation surgery. Therefore, if DBS is approved for the treatment of depression, its benefits will have to be weighed against the risks. Epidural cortical stimulation is a variant of this technique where small electrical paddles are laid on the surface of the brain under the skull. Beneficial effects up to 6 months were observed in a pilot study of 5 patients.¹⁰

Summary and Conclusions

FDA-approved strategies for neuromodulation in patients with treatment-resistant MDD include ECT, TMS, and VNS. Recent advances in ECT permit more efficient brain stimulation with a lower risk of memory loss. TMS is a safe and effective acute option for patients with treatment-resistant MDD, although more information is needed about the combination of TMS and pharmacotherapy. VNS has not been shown to significantly reduce depressive symptoms in prospective randomized clinical trials, but it is an option for the long-term treatment of severe refractory depression.

The Role of Psychotherapy in the Management of Treatment-Resistant Depression

Michael E. Thase, MD

Inadequate treatment response among patients with depression is especially common for individuals who face difficulties in their personal lives, such as marital discord or recent divorce, lack of social support, limited resources, or maladaptive interpersonal styles or personality disorders. Demoralization that is caused by difficulties such as these may make it more difficult for patients to engage in the type of productive, collaborative treatment relationship that is necessary to attain the best possible outcome with antidepressant therapy. Psychosocial difficulties also contribute to an increased risk of treatment nonadherence. Psychotherapy provides an important method to help patients to address these obstacles. In addition, it is possible that psychotherapy and pharmacotherapy may complement one another by acting on different brain pathways. For example, it has been hypothesized that antidepressants initiate a clinical response primarily through brain stem-mediated mechanisms (a “bottom-up” approach), whereas psychotherapy improves depression by acting at higher cortical processes (a “top-down” approach).¹

Psychotherapy in the STAR*D Study

In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial, patients with inadequate response to citalopram were randomized to one of the several level-2 treatment options, which included either switching to another single-agent pharmacotherapy strategy, switching to cognitive behavior therapy (CBT), augmentation with another antidepressant, or the addition of CBT to pharmacotherapy.^2,3 CBT was selected as the psychotherapy option for this study because it is the best-studied form of psychotherapy for major depressive disorder (MDD), it provides standardized methods for training and for assessing therapy quality and outcomes, and the investigators who designed the study were certified cognitive therapists. In addition, preliminary research had suggested that CBT improves outcomes in patients with MDD who had not responded adequately to antidepressant therapy.⁴

In STAR*D, remission with citalopram monotherapy was attained by 33% of patients after 12 weeks. Residual depressive symptoms were classified as mild (28% of the patients), moderate (23%), severe (12%), or very severe (4%).² Patients with residual symptoms that were moderate to very severe were randomized to one of 7 treatment strategies, 4 of which employed switching to another monotherapy and 3 of which employed augmentation (Figure 1). An important feature of this study was that patients had the option to opt out of particular treatment strategies. For example, patients could choose to undergo CBT as augmentation but not as monotherapy, or to opt out of any CBT strategy. During the planning of the study, the investigators estimated that 20% to 30% of patients would choose not to participate in at least one treatment strategy. However, more than 90% of the patients enrolled in STAR*D opted out of at least one treatment. Most of the patients preferred either a switch to another monotherapy or augmentation as their next treatment step; few patients were open to being randomized to one or the other. As a result, it was not possible for the study to compare treatment outcomes for switching vs augmentation strategies. In addition, approximately two-thirds of the patients declined CBT as either a switching or augmentation strategy. In general, patients who opted for a monotherapy switch strategy received the least benefit from their initial therapy, whereas patients who opted for augmentation attained more benefit from initial therapy. Although the high rate of opting out of psychotherapy suggests that patients who are not responding to antidepressant therapy are generally not interested in exploring psychotherapy as the next treatment step, other factors may also have contributed to the high psychotherapy opt-out rate observed in STAR*D. For example, the psychotherapists and the pharmacotherapists were often located at different facilities, and the study could not pay insurance copayments for psychotherapy costs.

Despite the fact that two-thirds  of eligible patients opted out of receiving psychotherapy, STAR*D remains largest study of psychotherapy augmentation for treatment-resistant MDD ever conducted. The comparison of the rates of remission between CBT and pharmacotherapy treatments as augmentation revealed that the remission rates were similar for the CBT and pharmacotherapy strategies (Figure 2). For the patient-rated, 16-item Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR-16) rating scale, remission was noted for 31% of patients with CBT and 33% with medication augmentation (bupropion or buspirone). On the clinician-rated, 17-item Hamilton Rating Scale for Depression (HSRD-17), remission was noted for 23.1% of patients with CBT vs 33.3% for those who did not receive psychotherapy, which was not statistically significant.³ Although the overall remission rate by the end of treatment did not differ between the 2 strategies, the onset of effect was more rapid with medication augmentation. These data suggest that unless the patient is highly motivated to undergo psychotherapy, a medication augmentation strategy appears to offer more rapid symptomatic relief than psychotherapy augmentation.

For patients who were switched to monotherapy with CBT or pharmacotherapy as their second-step treatment, no differences were observed in clinical outcomes between CBT and pharmacotherapy for response or remission rates. On the patient-rated QIDS-SR-16, remission rates were 30.6% vs 26.7% for CBT and pharmacotherapy, respectively. For the clinician-rated HRSD-17, remission rates were 25.0% vs 27.9% for CBT and pharmacotherapy. Neither of these differences was statistically significant. In contrast with the augmentation strategy, there was no evidence that either CBT or pharmacotherapy led to a faster onset of remission.

Psychotherapy Issues in Refractory Depression

The goals of psychotherapy are to help to maintain and engage patients in productive, collaborative treatment relationships that are based on clearly focused goals and expectations. Some of these goals include increasing overall activity level and involvement in pleasurable events, helping with coping behaviors, improving treatment adherence, and improving problem-solving skills.⁵ CBT techniques focus on very basic behavioral strategies such as graded task assignments, and breaking large tasks down into smaller components. Psychoeducation is essential to ensure that the patient and family members have reasonable expectations about the likely effects of treatment. Finally, it is important for the clinician to avoid “blaming the victim” or deciding that the patient is not treatable. If the therapist begins to feel that a patient is untreatable, the likelihood that they will not respond to treatment increases. In this situation, a peer consultation may help identify alternate strategies for these more difficult-to-treat patients.

Summary and Conclusions

Although many clinicians believe that antidepressants produce a more rapid onset of effect than psychotherapy for MDD, the STAR*D study found that, at least in this population of difficult-to-treat patients, there was only a small difference in time to remission in the augmentation strategy, and no difference in the monotherapy switch strategy.

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