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Nefazodone therapy in patients with treatment-resistant or treatment-intolerant depression and high psychiatric comorbidity
CLINICAL THERAPEUTICSVVOL.
21, NO. 4,1999
Nefazodone Therapy in Patients with Treatment-Resistant or Treatment-Intolerant Depression and High Psychiatric Comorbidity Martha Sajatovic, MD:-3 Sue DiGiovanni, MD,‘z Matthew Fuller, PharmD,‘J Joan Belton, SW,’ Eva DeVega, MSN,’ Sybille Marqua, MD,‘z and David Liebling, MD12 ‘Department of Veterans Affairs Medical Center, Psychiatry Service, 2Case Western Reserve University, and 3Northcoast Behavioral Healthcare System, Cleveland, Ohio
ABSTRACT Given the potentially severe functional impairment, morbidity, and high costs associated with refractory depression, it is important to explore all treatment options that may benefit patients with this disorder. This is a retrospective, uncontrolled analysis of our experience with nefazodone therapy in treatment-resistant and treatment-intolerant depression. Potential candidates for nefazodone therapy were referred by their treating psychiatrist. Documentation of failure to respond to previous antidepressant therapy, a diagnosis of clinical depression according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and completion of a Beck Depression Inventory (BDI) were required before initiation
Accepfed for publication Printed in the USA. Reproduction
0149.2918/99/$19.00
in whole
February
17, 7999.
or part is not permitted
of nefazodone. A follow-up BDI was obtained after 24 weeks of nefazodone therapy. A Clinical Global Inventory (CGI) score was obtained retrospectively based on documentation of target symptoms in the clinical record of the last clinic visit. The study group consisted of 20 patients with treatment-resistant or treatment-intolerant major depression who received nefazodone therapy. The mean (k SD) age of the group was 48.1 f 9.4 years. The mean number of previously failed antidepressant trials was 1.9 + 0.6. Psychiatric comorbidity in this group was substantial, with posttraumatic stress disorder (PTSD) found in 11 (55%) patients, substance abuse in 3 (15%) patients, and personality disorder found in 2 (10%) patients. After treatment with nefazodone, 11 of 20 patients (55%) were rated on the CGI as much or very much improved. In addition, 9 patients (45%) had >20% improvement on BDI, 3 patients (15%) had 10% to 20% improvement, and 6 patients (30%) had ~10% change. Two patients (10%) dis133
CLINICAL
continued nefazodone therapy due to adverse effects. Analysis of our experience with nefazodone therapy in a population with treatment-resistantdepressionand a high degree of psychiatric comorbidity suggeststhat approximately 50% of patients may have substantial responseto treatment, with a smaller proportion having a more modestclinical response.While receiving nefazodone therapy, most patients continued to take concurrently prescribed psychotropic medications,primarily anxiolytics or other antidepressants.Of interest was the positive drug response among a subgroupof individuals with depression and chronic, severe PTSD. Larger, controlled studies are needed to determine whether these preliminary observations are confirmed. Key words: treatment-resistant depression, nefazodone, posttraumatic stressdisorder, antidepressantmedication. INTRODUCTION Approximately 30% of patients with clinical depression fail to respond to treatment with an antidepressant.1-3Risk factors for treatment resistance include inadequatedosing or duration of pharmacologic treatment, noncompliance with therapy, and presence of comorbid psychiatric conditions.47 Previous lack of responseto antidepressanttherapy may also predict poor outcomes to subsequenttrials of antidepressants.* Although treatment-resistant depression is a common problem having substantial negative sequelae,systematic attention to the definition and management of refractory illnesshas beenlimited.5*x-‘0 Options in pharmacologic management include review of the case to determine whether previous failed antidepressant 734
THERAPEUTICS”
therapy was optimized, augmentation of therapy with additional psychotropic medication, and switching to an alternative antidepressantmedication. In clinical practice, augmentationof antidepressantmedication is often tried before switching to a different antidepressant. This method is effective in a number of cases,1’-13 although care must be taken to avoid adverseeffects relatedto polypharmacy,t4 and the risks of a given combination of medicationsmust be consideredin the context of suchcomorbid conditions as substanceabuse.7Switching antidepressant therapy should be considered if patients continue to experience depressive symptoms despiteoptimization or augmentation of ongoing antidepressanttherapy.l* Novel antidepressantssuch as nefazodone may give patients who have failed to respond to other treatment regimensa new opportunity for recovery. Clinically, nefazodone has been demonstratedto be an effective antidepressantis,‘6with minimal cardiac toxicity and minimal effects on sexual functioning.‘7,‘8 Nefazodone may have particular efficacy in individuals with comorbid symptoms of anxiety associatedwith depression,15*16*19 and has been reported to be beneficial in individuals with severe depression.20Given the potentially severe functional impairment, morbidity, and high costs associatedwith refractory depression, it is important to explore all treatment options that may be of benefit. This paper describesour experience with nefazodone therapy in patients with treatment-resistant or treatment-intolerant depression. PATIENTS AND METHODS At the time of the study, nefazodone therapy was prescribed at our facility in ac-
M. SAJATOVIC
ET AL.
cordancewith a quality-improvement protocol for the managementof patients with treatment-resistantor treatment-intolerant major depression. Treatment resistance was defined as lack of a significant clinical response to either 6 weeks of a tricyclic antidepressant at standard reference-range therapeutic blood levels (eg, nortriptyline 50 to 150 ng/mL)21 or 6 weeks of 1 of the 2 selective serotonin reuptake inhibitors (SSRIs) on our formulary (fluoxetine 40 mg/d and sertraline 200 mg/d). Potential candidates for nefazodone therapy were referred by their treating psychiatrist to a multidisciplinary quality-assurance committee of mental health care providers responsiblefor monitoring use of medications for the treatment of mood and anxiety disorders.Documentation of failure to respond to a previous antidepressanttrial, a diagnosis of clinical depressionaccording to criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,22 and completion of the Beck Depression Inventory (BDI),23 a 2 1-item, self-rated scale widely usedfor assessingthe severity of depressive illness (the higher the score, the greater the severity of depression), were required before committee approval to initiate treatment with nefazodone. After committee confirmation that patients were eligible for treatment with nefazodone, the dosing and titration of medication were at the discretion of the prescribing psychiatrist. A follow-up BDI was obtained after 24 weeks of nefazodone therapy at the next outpatient follow-up appointment (1 to 4 months after baseline). The Clinical Global Inventory (CGI),24 a widely used7-point instrument that assessesgeneral severity of illness and change over time (the higher the score, the greater the severity of illness),
was used retrospectively based on documentation of target symptoms in the clinical record. The study received appropriate institutional review board waiver of written informed consent. Data on dosageand duration of nefazodone treatment, reported adverseeffects, and use of concomitant medicationswere obtained from the electronic and paper progress notes, laboratory reports, and electronic pharmacy prescription tracking records. RESULTS The study group consistedof 20 patients with treatment-refractory or treatment-intolerant major depression who received nefazodone therapy; most patients had been chronically ill. Table I illustrates the demographic and clinical features of the patient group. The mean(+ SD) ageof the group was48.1 + 9.4 years (range 3 1 to 75 years). Previous antidepressantresponses included failure to respond to 21 antidepressantdrug (including sertraline, fluoxetine, tricyclic antidepressants,bupropion, or trazodone); 15patients(75%) had failed to respondto multiple (2 or 3) antidepressant trials. The mean (k SD) number of previous failed antidepressanttrials was 1.9 & 0.6. Most patientshad comorbid psychiatric conditions; posttraumatic stress disorder (PTSD) was diagnosedin 11 patients (55%), substanceabusein 3 patients (15%), and personality disorder in 2 patients (10%). Mean (+ SD) baselineCGI scoreswere 4.16 + 0.6 (range, 3 to 5). Mean (2 SD) follow-up CGI scores were 2.65 + 1.3 (range, 1 to 6) with 11of 20 patients (55%) rated much or very much improved, which corresponded to clinically significant change (P < 0.01). In this small sample, 735
CLINICAL
THERAPEUTICS”
Table I. Demographic and clinical characteristics of 20 subjectswith treatment-resistant or treatment-intolerant depression. Value
Variable
48.1 + 9.4
Age (Y) Sex, no. (%) Male Female Duration of illness (mo) Mood disorder diagnoses, no. (%) Major depression Bipolar disorder (type 1, depressed) Comorbid diagnoses, no. (%) Posttraumatic stress disorder Substance abuse disorder Personality disorder No. of comorbid diagnoses No. of previously failed antidepressant trials History of past antidepressant trials* Failed I antidepressant Failed 2 antidepressants Failed 3 antidepressants Beck Depression Inventory+ Baseline End point Clinical Global Inventorya Baseline End point Values are mean c SD, unless otherwise noted. *Antidepressant medications included sertraline, fluoxetine, ‘Higher scores indicate greater severity of illness. *P = 0.03 versus baseline. 8n = 19. Higher scores indicate greater severity of illness. IiP < 0.01 versus baseline.
response to nefazodone therapy did not appearto be related to the number of previous antidepressant trials or classesof drugs previously used. The mean (+ SD) BDI score before beginning nefazodone therapy was 30.5 + 8.7 (range, 12 to 46), the mean (+ SD) score at follow-up while receiving nefazodone therapy was 24.3 + 8.4 (range, 10 to 41) (P = 0.03). Forty736
19 (95) 1 (5) 25.7 f 21.4 17 (85) 3 (15) 11 (55) 3 (15) 2 (10) 0.9 f 0.5 1.9 k 0.6 5 (25) 12 (60) 3 (15) 30.5 f 8.7 24.3 f 8.4: 4.16 f 0.6 2.65 + 1.311
tricyclic
antidepressants,
bupropion,
and trazodone.
five percent of patients (n = 9) had >20% improvement in BDI score; 15% (n = 3) had 10% to 20% improvement, and 30% (n = 6) had ~10% change. Two patients (10%) discontinuednefazodone therapy due to adverse effects. Thesepatients were not included in the final analysis. One of thesepatientsdiscontinued therapy after 5 days at a nefazo-
M. SAJATOVIC
ET AL.
done dosageof 50 mgld. This individual was taking concomitant thioridazine therapy and developed sedationand orthostasis. Symptoms resolved with discontinuation of both thioridazine and nefazodone. A secondpatient discontinuednefazodone becauseof persistent sedation and loose stools after 3 months of nefazodone therapy (with minimal improvement in psychiatric symptoms) at 400 mg/d. Physical symptoms resolved after nefazodone discontinuation. Switching patients from SSRI therapy to nefazodone therapy was well tolerated, with no significant adverse effects that were judged by the unmasked investigators to be drug related. In the subgroup of 11 veterans with PTSD, 4 patients (36%) had >20% improvement in BDI score,2 patients (18%) had 10% to 20% improvement, and 5 patients (45%) had ~10% improvement. The mean (k SD) nefazodone dosageat follow-up was 287.5 + 144.1 mg/d (me-
dian, 300 mg/d; range, 50 to 450 mg/d). The mean (? SD) duration of treatment was 82 + 44.0 days (median, 72 days; range, 5 to 168 days). Most patients (n = 17, 85%) remained on nefazodone therapy at the time of follow-up. As might be expected from the high degree of comorbidity and treatment-refractory depression in this group, the use of concomitant psychotropic medications was common. Table II lists the type and proportion of concomitant medications used. In this small sample,there appearedto be no association between a positive nefazodone responseand the concomitant medications used.However, the meannefazodonedose was relatively low, which may have minimized potential drug-drug interactions. The mean (k SD) number of concomitant psychotropic medications (excluding nefazodone) was 1.3 f 1.l medications (range, 0 to 4); 5 patients (25%) were receiving monotherapy.
Table II. Concomitant medicationsprescribedduring nefazodone therapy. Medication None (nefazodone monotherapy) Other antidepressant+ Anxiolytic agenta Other antidepressant + anxiolytic agent Other antidepressant + anticholinergic agents Other antidepressant + mood stabilizer11 Anxiolytic + antipsychotic agent1 Anxiolytic + other antidepressant + antipsychotic agent Mood stabilizer + other antidepressant + antipsychotic agent + anticholinergic
No. of Patients*
agent
5 4 4 1 1 1 1 1 1
*Data were obtained for only 19 subjects. ‘Other antidepressants included sertraline, fluoxetine, trazodone, and bupropion. *Anxiolytic agents included buspirone, lorazepam, diazepam, and clonazepam. SAnticholinergic agents included benztropine and diphenhydramine. IiMood stabilizers included valproate and carbamazepine. IAntipsychotic agents included thioridazine, fluphenazine, and trifluperazine.
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DISCUSSION Interpretation of the data from this naturalistic study is limited by the small sample size, uncontrolled methodology that cannot exclude temporal changes as a cause of the results observed, use of concomitant medications, and lack of structured diagnostic interviews. Additionally, the point can be made that some patients, even those with comorbidities, may respond without medication. In spite of these limitations, some preliminary observations can be proposed. Analysis of our experience with nefazodone used as monotherapy or concomitantly with other psychotropic agents in a population of veterans with treatment-resistant or treatment-intolerant depression and a high degree of psychiatric comorbidity suggests that approximately 50% of patients may have a substantial response to treatment. Of interest is the positive drug response seen among a subgroup of individuals with depression and chronic, severe PTSD. These individuals generally are veterans who continue to be troubled by combat-related flashbacks, anxiety, irritability, and an exaggerated startle reflex. In typical clinical settings, these patients are often prescribed anxiolytic medications such as benzodiazepines. Although these medications may be effective for short-term use, problems associated with long-term use include drug dependence or lessening of efficacy in chronic conditions. As has been reported by others,19,23,25 nefazodone therapy may be efficacious in the management of depression with anxiety. Fontaine et ali5 reported that improvement in patient self-assessments of anxiety symptoms associated with depression was evident with nefazodone therapy as 738
early as the first week of treatment and was seen even at relatively low doses of nefazodone (50 to 250 mgid). Hertzberg et a126reported that nefazodone may be effective in treating PTSD in veterans, with an associated decrease in depressive symptoms and enhancement of sleep quality and duration. As in previous reports on safety and tolerability,17 nefazodone therapy was generally well tolerated in our population, with withdrawals for adverse effects occurring mainly because of sedation or orthostasis. Use of concomitant psychotropic medications could have contributed to the occurrence of adverse side effects in this sample. Possible measures to reduce the risk of sedation include reduction of doses of concomitant psychotropic medications (which may no longer be needed as nefazodone therapy is stabilized), and slow titration of nefazodone. CONCLUSIONS Nefazodone therapy may be a therapeutic option as augmentation therapy or as monotherapy in some patients with treatment-refractory or treatment-intolerant depression. It may be beneficial in individuals with comorbid anxiety symptoms, such as PTSD. Larger, controlled studies are needed to confirm these preliminary observations. ACKNOWLEDGMENTS This material is based on work supported by the Department of Veterans Affairs and Northcoast Behavioral Healthcare System, Cleveland, Ohio. The secretarial assistance of Mrs. Pamela Burton is greatly appreciated.
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ET AL.
Address correspondence to: Martha Sajatovic, MD, Northcoast Behavioral Healthcare System, Cleveland Campus, 1708 Southpoint Drive, Cleveland, OH 44109. REFERENCES 1. Fawcett J, Barkin RL. Efficacy issues with antidepressants. J Clin Psychiatry. 1997; 58(Suppl 6):32-39. 2. O’Reardon JP, Amsterdam JD. Treatmentresistant depression: Progress and limitrtions. Psychiatr Ann. 1998;28:633-640. 3. Nierenberg AA, White K. What next? A review of pharmacologic strategies for treatment resistant depression. Psychopharmacol Bull. 1991;26:429460. 4. Keller MB. Undertreatment of major depression. Psychopharmacol Bull. 1988;24: 75-80. 5. Guscott R, Grof P. The clinical meaning of refractory depression: A review for the clinician. Am J Psychiatry. 1991;148:695-704. 6. Hirschfeld RM, Keller MB, Panic0 S, et al. The National Depressive and ManicDepressive Association consensus statement on the undertreatment of depression. JAMA. 1997;277:333-340. Nunes EV, Deliuannides D, Donovan S, McGrath PJ. The management of treatment resistance in depressed patients with substance use disorders. Psychiatr Clin North Am. 1996;19:311-327. Homig-Rohan M , Amsterdam JD. Clinical and biological correlates of treatmentresistant depression: An overview. Psychiatr Ann. 1994;24:22&227. Nelson JC. Treatment of antidepressant nonresponders. Augmentation or switch? J Clin Psychiatry. 1998;59(Suppl 15):35-41.
10. Quitkin FM, McGrath PJ, Stewart JW, et al. Chronological milestones to guide drug change: When should clinicians switch antidepressants? Arch Gen Psychiatry. 1996;53:785-792. 11. Joffe RT, Schuller DR. An open study of buspirone augmentation of serotonin reuptake inhibitors in refractory depression. J Clin Psychiatry. 1993;54:269-271. 12. Zajecka JM, Jeffriess H, Fawcett J. The efficacy of fluoxetine combined with a heterocyclic antidepressant in treatment-resistant depression: A retrospective analysis. J Clin Psychiatry. 1995;56:338-343. 13. Fava M, Rosenbaum JF, McGrath PJ, et al. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: A double-blind, controlled study. Am J Psychiatry. 1994;151:1372-1374. 14. Jefferson JW. Drug interactions-friend or foe? J Clin Psychiatry. 1998;59(Suppl 4):3747. 15. Fontaine R, Ontiveros A, Elie R, et al. A double-blind comparison of nefazodone, imipramine, and placebo in major depression. J Clin Psychiatry. 1994;55:234-241. 16. Rickels K, Nefazodone pression: A Psychiatry.
Schweizer E, Clary C, et al. and imipramine in major deplacebo controlled trial. Br J 1994;164:802-805.
17. Robinson DS, Roberts DL, Smith JM, et al. The safety profile of nefazodone. J Clin Psychiatry. 19%;57(Suppl 2):31-38. 18. Feiger A, Kiev A, Shrivastava RK, et al. Nefazodone versus sertraline in outpatients with major depression: Focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry. 1996;57(Suppl 2):53-62.
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19. Fawcett J, Marcus RN, Anton SF, et al. Response of anxiety and agitation symptoms during nefazodone treatment of major depression. J Clin Psychiatry. 1995; 56(Suppl 6):3742. 20. Marcus RN, Mendels J. Nefazodone in the treatment of severe, melancholic, and recurrent depression. J Clin Psychiatry. 1996;57(Suppl 2): 19-23. 21. Fuller M, Sajatovic M. Drug Information Handbook for Psychiatry. 1st ed. Cleveland, Ohio: Lexi-Comp., Inc.; 1998. 22. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
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23. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-571. 24. Guy W. Clinical Global Inventory. In: Early Clinical Drug Evaluation Unit (ECDEU): Assessment Manual for Psychopharmacology (Revised). Washington, DC: US Department of Health, Education and Welfare; 1976. 25. Weiss KJ. Optimal management of anxiety in older patients. Drugs Aging. 1996; 9:191-201. 26. Hertzberg M, Feldman M, Beckman J, et al. Open trial of nefazodone treatment for post traumatic stress disorder. Presented at: New Clinical Drug Evaluation Unit (NCDEU) Program. May 28, 1997; Boca Raton, Fla.
21, NO. 4,1999
Nefazodone Therapy in Patients with Treatment-Resistant or Treatment-Intolerant Depression and High Psychiatric Comorbidity Martha Sajatovic, MD:-3 Sue DiGiovanni, MD,‘z Matthew Fuller, PharmD,‘J Joan Belton, SW,’ Eva DeVega, MSN,’ Sybille Marqua, MD,‘z and David Liebling, MD12 ‘Department of Veterans Affairs Medical Center, Psychiatry Service, 2Case Western Reserve University, and 3Northcoast Behavioral Healthcare System, Cleveland, Ohio
ABSTRACT Given the potentially severe functional impairment, morbidity, and high costs associated with refractory depression, it is important to explore all treatment options that may benefit patients with this disorder. This is a retrospective, uncontrolled analysis of our experience with nefazodone therapy in treatment-resistant and treatment-intolerant depression. Potential candidates for nefazodone therapy were referred by their treating psychiatrist. Documentation of failure to respond to previous antidepressant therapy, a diagnosis of clinical depression according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and completion of a Beck Depression Inventory (BDI) were required before initiation
Accepfed for publication Printed in the USA. Reproduction
0149.2918/99/$19.00
in whole
February
17, 7999.
or part is not permitted
of nefazodone. A follow-up BDI was obtained after 24 weeks of nefazodone therapy. A Clinical Global Inventory (CGI) score was obtained retrospectively based on documentation of target symptoms in the clinical record of the last clinic visit. The study group consisted of 20 patients with treatment-resistant or treatment-intolerant major depression who received nefazodone therapy. The mean (k SD) age of the group was 48.1 f 9.4 years. The mean number of previously failed antidepressant trials was 1.9 + 0.6. Psychiatric comorbidity in this group was substantial, with posttraumatic stress disorder (PTSD) found in 11 (55%) patients, substance abuse in 3 (15%) patients, and personality disorder found in 2 (10%) patients. After treatment with nefazodone, 11 of 20 patients (55%) were rated on the CGI as much or very much improved. In addition, 9 patients (45%) had >20% improvement on BDI, 3 patients (15%) had 10% to 20% improvement, and 6 patients (30%) had ~10% change. Two patients (10%) dis133
CLINICAL
continued nefazodone therapy due to adverse effects. Analysis of our experience with nefazodone therapy in a population with treatment-resistantdepressionand a high degree of psychiatric comorbidity suggeststhat approximately 50% of patients may have substantial responseto treatment, with a smaller proportion having a more modestclinical response.While receiving nefazodone therapy, most patients continued to take concurrently prescribed psychotropic medications,primarily anxiolytics or other antidepressants.Of interest was the positive drug response among a subgroupof individuals with depression and chronic, severe PTSD. Larger, controlled studies are needed to determine whether these preliminary observations are confirmed. Key words: treatment-resistant depression, nefazodone, posttraumatic stressdisorder, antidepressantmedication. INTRODUCTION Approximately 30% of patients with clinical depression fail to respond to treatment with an antidepressant.1-3Risk factors for treatment resistance include inadequatedosing or duration of pharmacologic treatment, noncompliance with therapy, and presence of comorbid psychiatric conditions.47 Previous lack of responseto antidepressanttherapy may also predict poor outcomes to subsequenttrials of antidepressants.* Although treatment-resistant depression is a common problem having substantial negative sequelae,systematic attention to the definition and management of refractory illnesshas beenlimited.5*x-‘0 Options in pharmacologic management include review of the case to determine whether previous failed antidepressant 734
THERAPEUTICS”
therapy was optimized, augmentation of therapy with additional psychotropic medication, and switching to an alternative antidepressantmedication. In clinical practice, augmentationof antidepressantmedication is often tried before switching to a different antidepressant. This method is effective in a number of cases,1’-13 although care must be taken to avoid adverseeffects relatedto polypharmacy,t4 and the risks of a given combination of medicationsmust be consideredin the context of suchcomorbid conditions as substanceabuse.7Switching antidepressant therapy should be considered if patients continue to experience depressive symptoms despiteoptimization or augmentation of ongoing antidepressanttherapy.l* Novel antidepressantssuch as nefazodone may give patients who have failed to respond to other treatment regimensa new opportunity for recovery. Clinically, nefazodone has been demonstratedto be an effective antidepressantis,‘6with minimal cardiac toxicity and minimal effects on sexual functioning.‘7,‘8 Nefazodone may have particular efficacy in individuals with comorbid symptoms of anxiety associatedwith depression,15*16*19 and has been reported to be beneficial in individuals with severe depression.20Given the potentially severe functional impairment, morbidity, and high costs associatedwith refractory depression, it is important to explore all treatment options that may be of benefit. This paper describesour experience with nefazodone therapy in patients with treatment-resistant or treatment-intolerant depression. PATIENTS AND METHODS At the time of the study, nefazodone therapy was prescribed at our facility in ac-
M. SAJATOVIC
ET AL.
cordancewith a quality-improvement protocol for the managementof patients with treatment-resistantor treatment-intolerant major depression. Treatment resistance was defined as lack of a significant clinical response to either 6 weeks of a tricyclic antidepressant at standard reference-range therapeutic blood levels (eg, nortriptyline 50 to 150 ng/mL)21 or 6 weeks of 1 of the 2 selective serotonin reuptake inhibitors (SSRIs) on our formulary (fluoxetine 40 mg/d and sertraline 200 mg/d). Potential candidates for nefazodone therapy were referred by their treating psychiatrist to a multidisciplinary quality-assurance committee of mental health care providers responsiblefor monitoring use of medications for the treatment of mood and anxiety disorders.Documentation of failure to respond to a previous antidepressanttrial, a diagnosis of clinical depressionaccording to criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,22 and completion of the Beck Depression Inventory (BDI),23 a 2 1-item, self-rated scale widely usedfor assessingthe severity of depressive illness (the higher the score, the greater the severity of depression), were required before committee approval to initiate treatment with nefazodone. After committee confirmation that patients were eligible for treatment with nefazodone, the dosing and titration of medication were at the discretion of the prescribing psychiatrist. A follow-up BDI was obtained after 24 weeks of nefazodone therapy at the next outpatient follow-up appointment (1 to 4 months after baseline). The Clinical Global Inventory (CGI),24 a widely used7-point instrument that assessesgeneral severity of illness and change over time (the higher the score, the greater the severity of illness),
was used retrospectively based on documentation of target symptoms in the clinical record. The study received appropriate institutional review board waiver of written informed consent. Data on dosageand duration of nefazodone treatment, reported adverseeffects, and use of concomitant medicationswere obtained from the electronic and paper progress notes, laboratory reports, and electronic pharmacy prescription tracking records. RESULTS The study group consistedof 20 patients with treatment-refractory or treatment-intolerant major depression who received nefazodone therapy; most patients had been chronically ill. Table I illustrates the demographic and clinical features of the patient group. The mean(+ SD) ageof the group was48.1 + 9.4 years (range 3 1 to 75 years). Previous antidepressantresponses included failure to respond to 21 antidepressantdrug (including sertraline, fluoxetine, tricyclic antidepressants,bupropion, or trazodone); 15patients(75%) had failed to respondto multiple (2 or 3) antidepressant trials. The mean (k SD) number of previous failed antidepressanttrials was 1.9 & 0.6. Most patientshad comorbid psychiatric conditions; posttraumatic stress disorder (PTSD) was diagnosedin 11 patients (55%), substanceabusein 3 patients (15%), and personality disorder in 2 patients (10%). Mean (+ SD) baselineCGI scoreswere 4.16 + 0.6 (range, 3 to 5). Mean (2 SD) follow-up CGI scores were 2.65 + 1.3 (range, 1 to 6) with 11of 20 patients (55%) rated much or very much improved, which corresponded to clinically significant change (P < 0.01). In this small sample, 735
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THERAPEUTICS”
Table I. Demographic and clinical characteristics of 20 subjectswith treatment-resistant or treatment-intolerant depression. Value
Variable
48.1 + 9.4
Age (Y) Sex, no. (%) Male Female Duration of illness (mo) Mood disorder diagnoses, no. (%) Major depression Bipolar disorder (type 1, depressed) Comorbid diagnoses, no. (%) Posttraumatic stress disorder Substance abuse disorder Personality disorder No. of comorbid diagnoses No. of previously failed antidepressant trials History of past antidepressant trials* Failed I antidepressant Failed 2 antidepressants Failed 3 antidepressants Beck Depression Inventory+ Baseline End point Clinical Global Inventorya Baseline End point Values are mean c SD, unless otherwise noted. *Antidepressant medications included sertraline, fluoxetine, ‘Higher scores indicate greater severity of illness. *P = 0.03 versus baseline. 8n = 19. Higher scores indicate greater severity of illness. IiP < 0.01 versus baseline.
response to nefazodone therapy did not appearto be related to the number of previous antidepressant trials or classesof drugs previously used. The mean (+ SD) BDI score before beginning nefazodone therapy was 30.5 + 8.7 (range, 12 to 46), the mean (+ SD) score at follow-up while receiving nefazodone therapy was 24.3 + 8.4 (range, 10 to 41) (P = 0.03). Forty736
19 (95) 1 (5) 25.7 f 21.4 17 (85) 3 (15) 11 (55) 3 (15) 2 (10) 0.9 f 0.5 1.9 k 0.6 5 (25) 12 (60) 3 (15) 30.5 f 8.7 24.3 f 8.4: 4.16 f 0.6 2.65 + 1.311
tricyclic
antidepressants,
bupropion,
and trazodone.
five percent of patients (n = 9) had >20% improvement in BDI score; 15% (n = 3) had 10% to 20% improvement, and 30% (n = 6) had ~10% change. Two patients (10%) discontinuednefazodone therapy due to adverse effects. Thesepatients were not included in the final analysis. One of thesepatientsdiscontinued therapy after 5 days at a nefazo-
M. SAJATOVIC
ET AL.
done dosageof 50 mgld. This individual was taking concomitant thioridazine therapy and developed sedationand orthostasis. Symptoms resolved with discontinuation of both thioridazine and nefazodone. A secondpatient discontinuednefazodone becauseof persistent sedation and loose stools after 3 months of nefazodone therapy (with minimal improvement in psychiatric symptoms) at 400 mg/d. Physical symptoms resolved after nefazodone discontinuation. Switching patients from SSRI therapy to nefazodone therapy was well tolerated, with no significant adverse effects that were judged by the unmasked investigators to be drug related. In the subgroup of 11 veterans with PTSD, 4 patients (36%) had >20% improvement in BDI score,2 patients (18%) had 10% to 20% improvement, and 5 patients (45%) had ~10% improvement. The mean (k SD) nefazodone dosageat follow-up was 287.5 + 144.1 mg/d (me-
dian, 300 mg/d; range, 50 to 450 mg/d). The mean (? SD) duration of treatment was 82 + 44.0 days (median, 72 days; range, 5 to 168 days). Most patients (n = 17, 85%) remained on nefazodone therapy at the time of follow-up. As might be expected from the high degree of comorbidity and treatment-refractory depression in this group, the use of concomitant psychotropic medications was common. Table II lists the type and proportion of concomitant medications used. In this small sample,there appearedto be no association between a positive nefazodone responseand the concomitant medications used.However, the meannefazodonedose was relatively low, which may have minimized potential drug-drug interactions. The mean (k SD) number of concomitant psychotropic medications (excluding nefazodone) was 1.3 f 1.l medications (range, 0 to 4); 5 patients (25%) were receiving monotherapy.
Table II. Concomitant medicationsprescribedduring nefazodone therapy. Medication None (nefazodone monotherapy) Other antidepressant+ Anxiolytic agenta Other antidepressant + anxiolytic agent Other antidepressant + anticholinergic agents Other antidepressant + mood stabilizer11 Anxiolytic + antipsychotic agent1 Anxiolytic + other antidepressant + antipsychotic agent Mood stabilizer + other antidepressant + antipsychotic agent + anticholinergic
No. of Patients*
agent
5 4 4 1 1 1 1 1 1
*Data were obtained for only 19 subjects. ‘Other antidepressants included sertraline, fluoxetine, trazodone, and bupropion. *Anxiolytic agents included buspirone, lorazepam, diazepam, and clonazepam. SAnticholinergic agents included benztropine and diphenhydramine. IiMood stabilizers included valproate and carbamazepine. IAntipsychotic agents included thioridazine, fluphenazine, and trifluperazine.
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DISCUSSION Interpretation of the data from this naturalistic study is limited by the small sample size, uncontrolled methodology that cannot exclude temporal changes as a cause of the results observed, use of concomitant medications, and lack of structured diagnostic interviews. Additionally, the point can be made that some patients, even those with comorbidities, may respond without medication. In spite of these limitations, some preliminary observations can be proposed. Analysis of our experience with nefazodone used as monotherapy or concomitantly with other psychotropic agents in a population of veterans with treatment-resistant or treatment-intolerant depression and a high degree of psychiatric comorbidity suggests that approximately 50% of patients may have a substantial response to treatment. Of interest is the positive drug response seen among a subgroup of individuals with depression and chronic, severe PTSD. These individuals generally are veterans who continue to be troubled by combat-related flashbacks, anxiety, irritability, and an exaggerated startle reflex. In typical clinical settings, these patients are often prescribed anxiolytic medications such as benzodiazepines. Although these medications may be effective for short-term use, problems associated with long-term use include drug dependence or lessening of efficacy in chronic conditions. As has been reported by others,19,23,25 nefazodone therapy may be efficacious in the management of depression with anxiety. Fontaine et ali5 reported that improvement in patient self-assessments of anxiety symptoms associated with depression was evident with nefazodone therapy as 738
early as the first week of treatment and was seen even at relatively low doses of nefazodone (50 to 250 mgid). Hertzberg et a126reported that nefazodone may be effective in treating PTSD in veterans, with an associated decrease in depressive symptoms and enhancement of sleep quality and duration. As in previous reports on safety and tolerability,17 nefazodone therapy was generally well tolerated in our population, with withdrawals for adverse effects occurring mainly because of sedation or orthostasis. Use of concomitant psychotropic medications could have contributed to the occurrence of adverse side effects in this sample. Possible measures to reduce the risk of sedation include reduction of doses of concomitant psychotropic medications (which may no longer be needed as nefazodone therapy is stabilized), and slow titration of nefazodone. CONCLUSIONS Nefazodone therapy may be a therapeutic option as augmentation therapy or as monotherapy in some patients with treatment-refractory or treatment-intolerant depression. It may be beneficial in individuals with comorbid anxiety symptoms, such as PTSD. Larger, controlled studies are needed to confirm these preliminary observations. ACKNOWLEDGMENTS This material is based on work supported by the Department of Veterans Affairs and Northcoast Behavioral Healthcare System, Cleveland, Ohio. The secretarial assistance of Mrs. Pamela Burton is greatly appreciated.
M. SAJATOVIC
ET AL.
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