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- 1. Hilik Levkovitz MD Professor Director Day Hospital & Cognitive and Emotional Lab. School of Medicine, Tel Aviv University, Israel.
- 2. First-Step Strategies in MDD: “An antidepressant medication is recommended as an initial treatment choice for patients with mild to moderate MDD and defintely should be provided for those with severe MDD…. For most patients SSRI, SNRI, Mirtazapine or Bupropion is optimal “ APA Guidelines for MDD , Am J Psyc. 2010
- 3. First-Step Strategies in MDD: Based on page 33 APA Guidelines for MDD , Am J Psyc. 2010 SSRI SNRI Mirtazapine Buproprion TCA = < fatigue and sleepiness < quite smoking < overweight or obese < sexual problem < agitation < anxiety < sexual problem < melancholia < severe depression < hospitalized
- 4. What makes a clinician a great clinician? Great clinician uses measurement-based care Identify putative moderators of treatment response to improved patient outcomes Optimizes each treatment step before moving to the next step
- 5. Measurement-based care in MDD Measurement-based care, may enhance the quality of care and improve clinical outcome. APA Guidelines for MDD , Am J Psyc. 2010 Trivedi MH, Neuropsychopharmacology. 2007
- 6. What Are Moderators? Moderators are baseline variables that predict response to treatment.
- 7. Moderators can be prognostic or prescriptive. • Prognostic moderators predict relative response regardless of the type of treatment. • Prescriptive moderators predict differential response to particular treatments.
- 8. Remission Rates in Anxious Vs. Non-anxious Depression Remission rates per HDRS, % P<0.0001 P<0.0001 0 5 10 15 20 25 30 35 40 45 50 fava et al. papacostas and lamen anxious depression nonanxious depression Patients with anxious depression have been shown to have significantly lower remission rates than those without anxiety Prognostic moderators
- 9. Prognostic moderators that have a less robust response : • Chronic Depression • Low intelligence • Older age (>40 years) • Limited education • Living alone/being unmarried • Unemployed • Comorbidities such as: Drug and alcohol abuse Vascular depression Cluster A personality disorders PTSD Provide more intensive treatment or move patients more rapidly through treatment stages Prognostic moderators
- 10. Demographic variables • Gender • Age • Menopausal status Prescriptive moderators: Predict response to specific antidepressant treatments
- 11. Remission Rates for Woman with Depression According to Age and Menopausal Status variable placebo SSRI SNRI >50 years ≥50 years + HRT - HRT 26% 17 % 36 % 44 % 48% 44% 50% 28 % 35% 27 % 20 % 16 % Older woman who is not taking HRT should typically be treated with an SNRI, not an SSRI Predict response to specific antidepressant treatments Prescriptive moderators Thase et al
- 12. Illness features • Subtype • Age at onset • Chronicity • Severity Prescriptive moderators :
- 13. Remission Rates With SSRIs Vs. TCAs in Melancholic MDD Remission rates, % 0 10 20 30 40 50 60 70 DUAG 1986 DUAG 1990 ROOSE 1994 SSRI TCA Patients with melancholic features of depression are more likely to respond to TCAs than to MAOIs or SSRIs Prescriptive moderators Predict response to specific antidepressant treatments
- 14. 1. Start with an SNRI (venlafaxine or duloxetine) 2. Move quickly to a TCA (eg, nortriptyline, plasma level = 120– 150 ng/ml) 3. Augment with lithium 4. Switch to clomipramine (± lithium) In patients with melancholic depression, CBT monotherapy would preferably not be used; however, CBT could be combined with medication. Treating patients with melancholic depression Perry PJ J Affect Disord. 1996 Prognostic moderators
- 15. Prescriptive moderators: Severity of depression In severe depression, APA guidelines recommend the use of antidepressants with psychotherapy rather than psychotherapy alone.
- 16. Prescriptive moderator Moderators favoring cognitive therapy over antidepressants (in mild to moderate depression): Unemployed Married Multiple recent stressful life events Fournier J Consult Clin Psychol. 2009
- 17. What makes a clinician a great clinician? Great clinician uses measurement-based care Identify putative moderators of treatment response to improved patient outcomes Optimizes each treatment step before moving to the next step
- 18. STAR*D Algorithm INITIAL TREATMENT: citalopram for up to 14 weeks SWITCH TO: bupropion, cognitive therapy, sertraline, venlafaxine OR AUGMENT WITH: bupropion, buspirone, cognitive therapy (Only for those receiving cognitive therapy in Level 2) SWITCH TO: bupropion or venlafaxine (if exiting Level 2a) SWITCH TO: mirtazapine or nortriptyline OR AUGMENT WITH: lithium or triiodothyronine SWITCH TO: tranylcypromine or mirtazapine combined with venlafaxine Level 1 Level 2 Level 3 Level 4 Level 2a Trivedi et al Am J Psychiatry 2006;163:28-40. Sinyor et al.. Can J Psychiatry 2010; 55:126-135.
- 19. Overall Remission Rates by Treatment Steps 36.8 30.6 13.7 13.0 0 10 20 30 Level 1 Level 2 Remission (%) Level 3 Level 4 40 Rush et al. Am J Psychiatry 2006; 163:1905–1917
- 20. There May be a Correlation Between Volumetric Changes in MDD and Clinical Symptoms Vasic et al. J Affect Disord 2008;109(1-2):107-16.). Comparison of 15 MDD subjects and 14 healthy controls -0.1 -0.05 0 0.05 0.1 15 17 19 21 23 25 27 29 31 Adjusted VBM Responses MADRS Score -0.1 -0.05 0 0.05 0.1 15 17 19 21 23 25 27 29 31 Adjusted VBM Responses MADRS Score DLPFC (BA 46) MOPFC (BA 11) Regions showing a negative correlation between gray matter concentration and depression severity
- 21. Major Depressive Disorder is Associated With Significant Functional Impairment Overall Functional Impairment as Reported by MDD Patients (n=622) Kessler et al. JAMA 2003;289(23):3095–105. Very Severe 19.1% Severe 40.2% None 3.1% Mild 9.5% Moderate 28.1% • Most (96.9%) respondents with 12-month MDD reported at least some role impairment • More than half (59.3%) of respondents with 12-month MDD reported severe to very severe impairment
- 22. “TRD” been removed from guidance ◦Now “Sequencing treatments after initial inadequate response”
- 24. Responders at endpoint on imipramine, fluoxetine and placebo evolve response at same rate Stassen et al 1993, Tollefson et al 1994 20% improvement at 1 week predicts responder at 4 weeks in 70% Stassen et al 1993 Prognostic moderators
- 25. Second-Step Strategies: • Increasing the dose • Switching • Combining two antidepressants • Augmentation.
- 26. No evidence of increased efficacy with higher doses in fixed dose studies of fluoxetine No significant advantage to raising dose of fluoxetine from 20mg to 60mg in non- responders at 2 weeks Fixed dose study Low fixed dose study Fluoxetine efficacy: low versus high dose No advantage for raising dose Wernicke et al 1989 Int Clin Psychopharmacol 4 S1
- 27. Fixed dose studies show no increased response with higher dose fluoxetine no sertraline no citalopram no duloxetine no venlafaxine no ? escitalopram yes
- 28. Ruhe et al. Neuropsychopharmachology 2009
- 29. Ruhe et al. Neuropsychopharmachology 2009
- 30. Second-Step Strategies: • Increasing the dose • Switching • Combining two antidepressants • Augmentation.
- 31. Second-Step Strategies: • Increasing the dose • Switching • Combining two antidepressants • Augmentation.
- 32. Second-Step Strategies: Combining two antidepressants Rush et al. Am. J. Psychiatry July 2011
- 40. Meta-Analysis of Response Rates of Atypical Antipsychotic Agents in Treatment-Resistant Major Depressive Disorder The overall pooled response rate for treatment with an atypical agent was 44.2%, compared with 29.9% for placebo. Nelson & Papakostas . Am . J. Psychiatry 2009
- 52. Am J Psychiatry. 2010 Jul 1. S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M 73 non-responder to SSRI with MDD 6-week trial 800 mg/twice a day Response and remission were higher for adjunctive SAMe than placebo (response rate 36.1% vs. 17.6, remission rate 28.5 vs. 11.7) Well-tolerated.
- 55. A dose-ranging study (n=711) identified agomelatine 25mg daily as the target dose when com-pared with agomelatine 1mg and 5mg daily In the first study, 212 patients received agomelatine (n=106) or placebo (n=105). For the ITT population the between group difference for the mean final HAMD scores was 2.30 (S.E. 1.02), p=0.026. In the second study, 238 patients received agomelatine (n=118) or placebo (n=120). For the ITT population the between group difference for the mean final HAMD scores was 3.44 (S.E. 0.92), p<0.001 Zajecka J. J Clin Psychopharmacol. 2010, Stahl SM J Clin Psychiatry. 2010 Kennedy SH Eur Neuropsychopharmacol. 2006 Agomelatine: a novel atypical antidepressant
- 57. First-Step Strategies in MDD: Based on page 33 APA Guidelines for MDD , Am J Psyc. 2010 SSRI SNRI Mirtazapine Buproprion TCA = < fatigue and sleepiness < quite smoking < overweight or obese < sexual problem < agitation < anxiety < sexual problem < melancholia < severe depression < hospitalized
- 58. Conclusions: Use measurement-based care Try to identify prognostic and prescriptive moderators Optimizes each treatment step
- 59. Thanks !!!
Notas del editor
- In this discussion, we will focus on new options for augmentation of psych therapeutic interventions with medication therapy in the setting of refractory depression. The learning objectives for this program are to review the epidemiology definition and clinical treatments available for treatment-resistant depression, to assess the benefits and limitations of resistant therapeutic strategies and therapies for depression, and finally, to discuss new data regarding the augmentation of current antidepressant therapies
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Thase et al10 compared antidepressant efficacy of SSRIs and an SNRI by patient age (< 50 years vs ≥ 50 years), gender, and HRT status. With SSRIs, remission rates were similar (about 36%) among men of both age groups and women less than 50 years of age, but older women had lower remission rates (28%). With the SNRI, remission rates were lower for older men (41%), similar for younger men and women (about 45%), and highest for older women (48%). When remission rates among older women were analyzed by HRT status, women not taking HRT had higher remission rates with the SNRI than with SSRIs, whereas women taking HRT showed less difference in remission rates between the 2 treatments (AV 2AV 2).
- Thase et al10 compared antidepressant efficacy of SSRIs and an SNRI by patient age (< 50 years vs ≥ 50 years), gender, and HRT status. With SSRIs, remission rates were similar (about 36%) among men of both age groups and women less than 50 years of age, but older women had lower remission rates (28%). With the SNRI, remission rates were lower for older men (41%), similar for younger men and women (about 45%), and highest for older women (48%). When remission rates among older women were analyzed by HRT status, women not taking HRT had higher remission rates with the SNRI than with SSRIs, whereas women taking HRT showed less difference in remission rates between the 2 treatments (AV 2AV 2).
- Thase et al10 compared antidepressant efficacy of SSRIs and an SNRI by patient age (< 50 years vs ≥ 50 years), gender, and HRT status. With SSRIs, remission rates were similar (about 36%) among men of both age groups and women less than 50 years of age, but older women had lower remission rates (28%). With the SNRI, remission rates were lower for older men (41%), similar for younger men and women (about 45%), and highest for older women (48%). When remission rates among older women were analyzed by HRT status, women not taking HRT had higher remission rates with the SNRI than with SSRIs, whereas women taking HRT showed less difference in remission rates between the 2 treatments (AV 2AV 2).
- Patients with melancholic features of depression are more likely to respond to TCAs than to MAOIs or SSRIs. Several studies found greater remission rates with TCAs than with SSRIs in patients with melancholic depression (AV 3AV 3).11 SSRIs should not be used in patients with melancholic depression unless a compelling reason exists. However, SNRIs can be tried briefly before switching to a TCA.
- Thase et al10 compared antidepressant efficacy of SSRIs and an SNRI by patient age (< 50 years vs ≥ 50 years), gender, and HRT status. With SSRIs, remission rates were similar (about 36%) among men of both age groups and women less than 50 years of age, but older women had lower remission rates (28%). With the SNRI, remission rates were lower for older men (41%), similar for younger men and women (about 45%), and highest for older women (48%). When remission rates among older women were analyzed by HRT status, women not taking HRT had higher remission rates with the SNRI than with SSRIs, whereas women taking HRT showed less difference in remission rates between the 2 treatments (AV 2AV 2).
- Patients with melancholic features of depression are more likely to respond to TCAs than to MAOIs or SSRIs. Several studies found greater remission rates with TCAs than with SSRIs in patients with melancholic depression (AV 3AV 3).11 SSRIs should not be used in patients with melancholic depression unless a compelling reason exists. However, SNRIs can be tried briefly before switching to a TCA.
- Patients with melancholic features of depression are more likely to respond to TCAs than to MAOIs or SSRIs. Several studies found greater remission rates with TCAs than with SSRIs in patients with melancholic depression (AV 3AV 3).11 SSRIs should not be used in patients with melancholic depression unless a compelling reason exists. However, SNRIs can be tried briefly before switching to a TCA.
- PURPOSE OF THE SLIDE To provide details about the STAR*D design and the treatments that were administered KEY POINTS Study used outcome based measures by patient self-report (Quick Inventory for Depression Self Report 16) to guide treatment decisions If patients did not achieve remission at one step, they were eligible for the next step in treatment Patients could not select the specific treatment but they could select what treatment intervention that they were willing to be randomly assigned `Patients who did not elect to go into a next step were naturalistically followed for up to 12 months At Step 2, patient preference had a strong role in their selection of acceptable treatment options; only 12% of patients would allow any type of treatment (switching or adjunctive treatment); of patients with preference, about half would only accept adjunctive treatment and half would accept switching (Wisniewski et al. 2007) At Step 2, willingness to augment versus switch was driven primarily by patients response to citalopram and its tolerability (Wisniewski et al. 2007)REFERENCESTrivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice.Am J Psychiatry 2006;163:28-40.Sinyor M, Schaffer A, Levitt A. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: A review.Can J Psychiatry 2010;55:126-35 Wisniewski SR, Fava M, Trivedi MH, Thase ME et al. Acceptability of second step treatment to depressed outpatients: A STAR*D report. Am J Psychiatry 2007; 164:753-760.
- PURPOSE OF THE SLIDE To describe the main primary outcome from each intervention step in the STAR*D studyKEY POINTS The primary outcome measure was the patient self-report Quick Inventory for Depressive Symptomatology 16 Items (QIDS-SR16)Secondary efficacy was measured by the Hamilton Depression Rating Scale – 17 itemsOverall remission rates decreased at each subsequent level in the study. Remission rates after Step 1 and Step 2 were each approximately 30%, but remission rates for those who went through Step 3 and 4 were about half, indicating a more treatment-resistant illness after 2 failed treatmentsThese results highlight the need for not only more effective acute treatments to achieve remission, but also more effective treatments to sustain remission over the long term.BACKGROUNDSTAR*D is a randomized antidepressant treatment trial in outpatients with MDD recruited from real-world clinical settings, enrolled 4011 outpatients aged 18-75 years with nonpsychotic MDD.The study was designed to determine which treatments were most effective after nonremission or intolerance to an initial SSRI or to any of a series of subsequent randomized treatments.STAR*D was conducted in 18 primary and 23 psychiatric care settings across the USA.REFERENCERush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW. Acute and longer-term outcomes in depressed outpatients requiring 1 or several treatment steps.: A STAR*D report. Am J Psychiatry 2006; 163:1905–1917Zisook S, Ganadjian K, Moutier C, Prather R, Rao S. Sequenced treatment alternatives to relieve depression (STAR*D): lessons learned. J Clin Psychiatry 2008;69:1184-85.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- We use the term augmentation typically to describe the use of an agent that is not per say antidepressant, but has psychotropic effects and is used to enhance the effects of the antidepressant itself. Augmentation strategies may vary. For example, by adding antianxiety effects or antidepressant effects and sometimes we combine agents with different mechanisms of action and/or indications.Now that you have provided us with your response, let me try to review for you a little bit of the literature on augmentation strategies.
- Lithium is probably the most studied augmentation strategy in the literature. Early reports in the literature dealing with monoamine oxidase inhibitors have suggested the usefulness of lithium augmentation. More recent studies, however, have challenged the usefulness of lithium, particularly with SSRIs and in addition the need for blood monitoring and the potential for toxicity of lithium have limited the use in the clinical practice. So although it is a very well-studied strategy, the overall kind of use of the strategy is rather modest
- Now let me show you another augmentation strategy that is relatively well studied and that is thyroid augmentation. We know that earlier studies with tricyclics have shown that thyroid augmentation, usually in the form of triiodothyronine (T3), 25-50 mcg a day was helpful in those 19 patients who had failed to respond to tricyclics. Subsequent studies have used SSRIs mostly in open label studies, not in randomized trials. And so one of the things that we were interested in the study was to actually see how thyroid and lithium augmentation would fair with SSRIs and selective norepinephrine reuptake inhibitors (SNRIs). And this is what we found in level 3 of STAR*D -- these are patients who did not respond at level 1 to citalopram, did not respond in level 2 to either switching or augmenting with buspirone or bupropion and now they are at the third level of kind of resistance if you wish and they are randomized to lithium and thyroid
- In this level 3 of STAR*D, it turns out that thyroid augmentation did a little bit better, with almost 10% higher remission rates, which was the outcome measure of the study. There was a significantly higher chance of a nonsignificantly higher chance of remission with T3 compared to lithium. And the lithium results were somewhat disappointing, suggesting that lithium, consistent with recent studies that have challenged the usefulness with SSRI in a patient is not particularly effective when added to an SSRI or SNRI.
- Buspirone is another commonly studied augmentation strategy. Buspirone is a silicone and fibrate C1A partial agonist typically used at 10-30 mg twice a day. The 2 placebo-control studies in the literature did not separate from placebo, but in 1 of the 2 studies, in the more severely ill population there was an advantage of buspironevs placebo.
- And this is of the reasons why we decided to study buspirone in patients in STAR*D. and in level two we randomized patients who hadn't responded to Citalopram to either buspirone augmentation or bupropion augmentation and in the study we found that the 2 treatments were pretty comparable in terms of remission rates. So, overall buspirone did as well as augmentation in the level 2 study.
- The next strategy that I will talk about is antipsychotic augmentation. A number of open label studies initially suggested the usefulness of this approach, and almost all of these patients were started on olanzapine, ziprasidone, quetiapine, and aripiprazole, often in doses that were used for other indications.[ CLOSE WINDOW ]Slide 13.Atypical Antipsychotic Augmentation
- Subsequently, Rick Shelton published a placebo-controlled study that showed that the advantage of olanzapine and fluoxetine combined was present only initially in an augmentation study; however, at the end of the study, the significance of the advantage was no longer present.
- Studies by Thase and other investigators using the dual augmentation approach with olanzapine and fluoxetine demonstrated an 8-week change in MADRS, as this slide illustrates.
- This was a study by Rob Berman that was published in The Journal of Clinical Psychiatry on aripiprazole, which showed a fairly robust effect of this drug compared to placebo in terms of both response and remission rates.
- A paper that came out this year from Ron Marcus and his group again showed that aripiprazole is superior to placebo in terms of improvement of depressive symptoms on the model scale. And these 2 studies led to the indication of aripiprazole for the adjunctive treatment of depression who have not responded to SSRIs. And this was the first real augmentation strategy approved by the US Food and Drug Administration with targeting the population of SSRI nonresponders.
- At a recent meeting, Dr. Bauer demonstrated the advantage of quetiapine over placebo as an augmentation.
- Another popular augmentation strategy among physicians is the dopaminergic drug augmentation. The action of D2/D3 agonists, with a pretty improved side effect profile has made these agents relatively popular among some clinicians and the studies thus far are only suggestive of efficacy because there are no double-blind placebo-controlled studies of these agents. There is 1 ongoing study by Dr. Perlis in our group that hopefully should wrap up in the next year or so.
- Methylphenidate is a psychostimulant that has an approval for attention deficit-hyperactivity disorder. But it is used kind of off label as it is occasionally lithium, or thyroid, or buspirone. The only published placebo controlled studies did not show us the physically significant difference between the methylphenidate and placebo in augmenting patients not responding to antidepressant treatment.
- Modafinil is a kind of wake promoting agent that has shown as an indication for narcolepsy and excessive sleepiness; however, it is also used off label in depression. This is a slide from a study that was conducted in patients who had only a partial response to an SSRI, but experienced residual fatigue and sleepiness. There was a significant advantage of modafinil over placebo. In what we have published in the past year we actually proved the data from the 2 placebo-controlled studies focusing on partial responders with persistent fatigue and sleepiness and in the polled analysis. But still it is an interesting analysis that allows us to the look at the efficacy of modafinil in this population. We did see an advantage of modafinil over placebo in most outcome measures
- In terms of anticonvulsant medication, the evidence is mostly antidotal or very small open label trials. There are almost no studies in resistant depression, even though these compounds are often used in combination with SSRIs to help anxious depression; for example, there is a study with zolpidem that shows greater effectiveness than placebo in augmenting SSRIs for people with residual insomnia. But in general, the experience in resistant depression is rather limited
- Our augmentation strategy to use methylfolate and some agents or compounds that are part of the on clinical cycle -- methylfolate is typically used at 7.5 mg, 1 or 2 tablets a day.
- And this was a study from our group, which was also an open label study dealing with the use of methionine.
- A study from Yale with riluzole suggested the potential usefulness of this group emergent compound, which is an N-methyl-D-aspartic acid receptor antagonist that is marketed for the treatments of amyotrophic lateral sclerosis, but it is used off label in very resistant patients. This is an open label study that hopefully will be replicated in a double-blind study.
- The remaining slides in this presentation illustrate an overview and key conclusions associated with current augmentation strategies
- The remaining slides in this presentation illustrate an overview and key conclusions associated with current augmentation strategies
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.
- Key Points in DiagnosisDrs. Charles Nemeroff, David Dunner, and A. John Rush all chaired symposia focused on TRD. Dr. Nemeroff, the Reunette W. Harris Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia,[3] and colleagues presented an overview of TRD.Dr. Nemeroff began by addressing the issue of diagnosis, stressing the need for clinicians to take a step back to ensure that their diagnosis is appropriate. He noted that, even if patients are referred with a diagnosis of TRD, that diagnosis may not be accurate; within his own practice, he has observed that approximately 30% of the patients referred to him who are labeled as treatment resistant are actually misdiagnosed or misreported.It is also important to rule out comorbid medical disorders such as hypothyroidism, which remains the number 1 cause of treatment resistance. Misdiagnosis also includes failure to identify the actual subtype of mood disorder, which is common, as is ruling out a diagnosis of atypical, psychotic, or bipolar depression. All of these considerations have an impact on treatment selection.In addition to ensuring that an appropriate diagnosis has been made, the importance of dosage and duration is often overlooked when evaluating this population. A dose should be adequate to achieve benefit and, in the case of nonresponders, pushed to highest tolerable levels; duration of treatment should often be extended to ensure that patients are given adequate time to respond. This principle of adequate dose and duration is often overlooked in the elderly population, which may take longer to respond, and in those with comorbid conditions, who may also take longer to respond and require higher dosages. Dr. Nemeroff also noted that one third of psychiatric outpatients enrolled in research studies have been described as noncompliant. He suggests drawing a blood level if there is a lack of response in order to determine whether a patient is compliant with antidepressant treatment.Several presenters[2,4,5] recommended the use of diagnostic staging for this population, in particular, the staging for antidepressant resistance offered by Dr. Thase and colleagues:Stage 1: Failure of an adequate trial of 1 class of major antidepressantStage 2: Failure of adequate trials of 2 distinctly different classes of antidepressantStage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA)Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI)Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT)Although many presenters underscored the importance of accurate diagnosis and emphasized the benefits of using measures, such as self-reported scales, for monitoring symptoms and function over time, fewer than 5% of physicians report using these scales in their practices.[6] A. John Rush, MD,[6] Betty Jo Hay Distinguished Chair in Mental Health, University of Texas Southwestern Medical Center in Dallas, also noted the importance of having an objective measure of symptom severity that can be compared at each visit. Typically familiar scales include: the Hamilton Depression Rating Scale (HAMD), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), and Improvement (CGI-I), all of which can be administered relatively easily and with little burden on the provider.With greater emphasis being placed on the use of rating scales, efforts have been made to simplify these scales so that some might even be integrated into primary care settings. Dr. Nemeroff discussed a study conducted last year in collaboration with Drs. McIntyre and Kennedy from Toronto. This pilot study examined the implementation of a 7-item HAMD scale in primary care practice. Primary care physicians in Canada administered either this shortened scale (requiring 3-4 minutes) or the longer HAMD-17 scale to study subjects. Of the 410 participating patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for major depressive disorder (MDD), half received the standard HAMD-17 and half received the HAMD-7. Results indicated a strong correlation between the HAMD-17 and the HAMD-7; 67% of HAMD-7 patients were classified as responders (50% reduction in pretreatment scores) compared with 74% of those who responded with the HAMD-17. These preliminary data indicate that the HAMD-7 may reduce the time required to administer the scale and still be useful in the diagnosis and recognition of depression.With respect to treatment choice, the selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment, with better side-effect profiles and tolerability. For those with TRD, TCAs and MAOIs are also included within the pharmaceutical treatment regimen. A number of combination and augmentation strategies are also employed in an effort to improve patient symptomatology.