TREATMENT RESISTANCE IN DEPRESSION AND PTSD
From Treatment-Resistant Disorders, presented by the American Academy of Clinical Psychiatrists
| TREATMENT-RESISTANT DEPRESSION —Mantosh Dewan, MD, Professor and Chair, Department of Psychiatry,
State University of New York Upstate Medical University, Syracuse
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| Background: response (defined as >50% improvement) relatively poor with first trial of any treatment; 50% of patients
undergoing psychotherapy improve, and 50% respond to medication; this response now considered inadequate
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 | Remission: new standard; <7 on Hamilton Depression Rating Scale (HAM-D); recent finding showing venlafaxine
more effective than selective serotonin reuptake inhibitors (SSRIs) does not hold up in “real world”
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| Factors associated with resistance
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| Psychotic depression: affects 15% of severely depressed patients; often missed; ask patients directly about psychotic
symptoms, eg, delusions, hallucinations; often linked with bipolar disorder; clues include frequent but brief episodes
and positive family history; prognosis poor (in one study, only 29% of patients returned to baseline within 2
yr); usually treated with antidepressants plus antipsychotics; electroconvulsive therapy (ECT) also effective
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| Bipolar depression: clues include early onset; short frequent episodes; motor retardation; reversal of sleep-wake cycle,
resulting in increased sleep; weight gain; family history of mania; consider patients bipolar even if they do not experience
full-blown mania; treat with mood stabilizers (lithium and lamotrigine), adding antidepressants only if necessary
because they may promote cycling; substance abuse common comorbidity; even moderate alcohol use
undermines prognosis; in adolescents, mood disturbances plus substance abuse risk factor for suicide; anxiety and
personality disorders also worsen prognosis (increased risk for suicide, lower response to treatment), but both common
depression comorbidities
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| Medical disorders: may complicate treatment of depression
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| Nutritional supplementation: some evidence it improves treatment response; folic acid—serum levels low in
some depressed patients; 800 mg bid or given in addition to SSRIs may help; vitamin B12 —prevalence of low serum
levels associated with depression severity in women; causative relationship suggested (controversial); rule out if patient
not responding to treatment
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| Optimizing response to treatment: noncompliance—biggest problem; associated with high risk for recurrence; remind
patients at every visit about its importance, even when they are feeling better; enlist help of loved ones, disease-
management programs, and psychotherapists; dose and duration—best responses associated with maximum doses (40
mg fluoxetine, 42 mg citalopram); 12- to 14-wk course recommended for severe chronic resistant depression; doses
above recommended maximum even more effective; side-effect management—promotes compliance; tricyclic antidepressants
(TCAs) vs SSRIs—TCAs coming back into favor in light of disappointing results with SSRIs; monitor blood
levels (150 ng associated with 30% response, but >225 ng associated with 93% response); augmentation vs switching—
if patient shows partial response to drug, augment dose (protects response already achieved; may convert partial response
to remission); if patient does not respond, switch (reasons include similar response rate, fewer side effects if using one
drug rather than 2, lower cost, and improved adherence)
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| Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: began with 2876 depressed patients;
doctors could change medications if necessary and use appropriate doses; patients had chronic severe intractable
depression plus many comorbidities; all patients began with 14-wk course of citalopram; aggressive treatment
encouraged; primary end point remission (score <7 on HAM-D), with Quick Inventory of Depressive Symptomatology,
Self-Report (QIDS-SR) as secondary end point (score <5 considered remission)
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| Results: first phase—mean exit dose 42 mg; response rate (50% improvement on HAM-D and QIDS-SR) 47%; remission
rates 28% (HAM-D) and 33% (QIDS-SR); second phase—patients who did not remit could choose to
augment with 1 of 4 medications, switch to 1 of 3 medications, or leave study (data on cognitive therapy not yet
published); 1439 patients participated, of whom 727 changed medications; duration 14 wk; new drugs long-acting bupropion
(≤400 mg/day), sertraline (≤200 mg/day), or long-acting venlafaxine (≤375 mg/day); response rates (QIDS-
SR)—26% (bupropion); 27% (sertraline); 28% (venlafaxine); remission rates (HAM-D)—21% (bupropion); 18%
(sertraline); 25% (venlafaxine); all in all, 50% to 55% of patients went into remission after 2 full trials of medication
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| Augmentation: 565 patients participated; their doses of citalopram increased to 55 mg/day (average; unusual for
normal clinical practice); patients also augmented with bupropion (≤400 mg/day) or buspirone (≤60 mg/day); response
rates (QIDS-SR)—with citalopram and bupropion 32%; with citalopram and buspirone 27%; remission
rates (HAM-D)—30% for both groups
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| Conclusions: response to augmentation slightly higher than switching drugs entirely; bupropion associated with significantly
greater reduction in number and severity of symptoms, fewer side effects, and lower dropout rate than
buspirone
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| Other augmenting strategies: can use lithium in dose >0.4 mEq; thyroid hormone (T3 works better than T4 ); response
rates for either drug 50% to 60% when combined with another antidepressant; Food and Drug Administration
(FDA) has approved combination of olanzapine plus fluoxetine; bromocriptine, estrogen, testosterone,
bopindolol, and modafinil show promise as augmenting agents
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| Receptor-based model for depression treatment: classic combination—includes lithium; hormone combination—
includes thyroid hormone; adrenergic combination—TCAs plus bupropion and possibly stimulants; cautious
combination—TCAs plus monoamine oxidase inhibitors; serotonin combination—start with SSRI; augment with
buspirone, mirtazapine, or trazodone; heroic combination—combination of 3 or even 4 antidepressants
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| Psychotherapy: first choice for treating mild to moderate depression; as effective as medication; associated with
lower rate of relapse after termination of treatment; some evidence that cognitive therapy prevents further relapses;
in study of 60 patients with moderate to severe depression who underwent cognitive therapy, 58% responded and
40% remitted; similar rates seen in 120 patients treated with paroxetine (58% responded, 46% remitted); for patients
with moderate to severe depression, psychotherapy can support pharmacotherapy, offer hope, help patients deal
with everyday stresses, and “not tilt the balance in favor of depression”; may encourage compliance
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| Optimizing psychotherapy: depression-specific therapy better than generic therapy; evidence suggests that brief dynamic
therapy effective in 35% of patients, compared to 47% of patients with cognitive therapy and 52% with interpersonal
therapy; in study of patients taught coping skills, 2-yr relapse rate 16%; therapist’s competence critical; important to
find therapists with experience in cognitive or interpersonal therapy (often difficult); evaluate patient after 6 wk, and
follow medication guidelines (switch to medication if no response; prolong psychotherapy if response partial); end
point of psychotherapy should be remission (<6 on HAM-D); of patients who remit on psychotherapy, 10% relapse
within 1 yr, compared to 50% of nonremitters; goal is symptom elimination
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| Cognitive Behavioral Assessment System (CBAS): combines best techniques of behavioral, cognitive, and interpersonal
psychotherapies for depression; results similar to those with each style alone
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| Sequence of medication and psychotherapy: in 12-wk double-blind randomized controlled trial of 454 patients treated
with CBAS or nefazodone, 140 (31%) who did not respond switched to other treatment; of 61 switched to CBAS,
53 completed; 57% of those patients did well (responded or remitted); 79 patients switched to nefazodone, 57 completed,
and 42% did well; difference statistically significant; suggests patients can do well starting on one modality
then switching to another
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| Combining medication and psychotherapy: indicated for chronic severe depression; associated with improvement
rates as high as 85%
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| Relapse prevention: 3 studies show that severely ill patients receiving ongoing medication and psychotherapy continue
to struggle but have lower overall rate of relapse than those on one treatment alone
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| Depression in elderly: nortriptyline plus interpersonal therapy associated with acute response rate of 66%, but patients
took up to 12 wk to respond (allow older patients more time before evaluating); combined treatment associated
with lower 1-yr relapse rates than single therapy; in later study of elderly patients randomized into 4 groups, relapse
rate 68% among those who received interpersonal therapy plus placebo during 2-yr follow-up, compared to 58% in
those receiving placebo and clinical management, 37% in those who received clinical management plus paroxetine,
and 35% in those receiving paroxetine and interpersonal therapy; conclusion—psychotherapy alone does not prevent
relapse in elderly; must be maintained on medications
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| Somatic treatments: 60% of medication-resistant patients respond to ECT, but 1-yr relapse rates 50% to 70%; maintenance
with medication necessary
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| Summary: look at diagnosis and subtypes; look for and treat comorbid conditions separately and aggressively; for patients
with severe treatment-resistant depression, combine medications or medication plus psychotherapy; use highest
tolerable doses; monitor compliance; finding therapists competent at depression-specific psychotherapy challenging;
focus on remission, not just response (may take time)
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| TREATMENT-RESISTANT POSTTRAUMATIC STRESS DISORDER (PTSD)—Lawrence A. Labbate, MD, Professor
of Psychiatry and Behavioral Sciences, University of Arkansas for Medical Sciences and Veterans Affairs Medical
Center, Little Rock
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| Epidemiology: ≈8% of Americans; war or combat most common causes in men; sexual assault most common cause in
women; usually accompanied by mood or anxiety disorders or substance abuse; persists for >10 yr in 40% of patients;
treatment outcomes poor, especially in combat-related cases
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| Limitations of clinical trials: often emphasize diminution of individual symptoms rather than overall improvement;
usually select milder cases to increase chances of good results; focus on effect size instead of cure
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| Clinician-Administered PTSD Scale (CAPS): uses Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) criteria for PTSD; rated on scale of 0 (no symptoms) to 4 (very severe symptoms); score
of 50 usually cutoff for entry into clinical trials; patients may be evaluated on change from baseline or relative to
comparison group; effect size calculated by dividing difference in scores between groups by score range (SD)
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| Limitations of effect size: patients may still have symptoms, despite significant differences in effect sizes between
groups; SDs may overlap (suggests at least some improvement due to nonspecific placebo effect); effect sizes
larger in psychotherapy than pharmacology studies (may not represent real-life patients); in study of women
PTSD patients randomized to 150 mg sertraline or placebo, 50% of patients taking sertraline experienced 30%
improvement; however, prevalence of drug or alcohol abuse only 25%, and major depression 33%; suggests these
patients “not particularly ill”; effect size moderate, with 75% overlap between groups; no reports of full remission;
question whether sertraline really treats PTSD
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| Paroxetine study: included 550 women randomized to one of several doses of paroxetine or placebo; no history of
drug or alcohol abuse, suicide attempts, or problems with SSRIs; effect sizes slightly better than those obtained in
sertraline study, but SDs large; paroxetine may have helped these patients, but mean final CAPS score 38, suggesting
they still had symptoms
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| Sertraline plus cognitive behavioral therapy (CBT): in small study of Cambodian refugees, those who received sertraline
alone got worse, while those who underwent combined treatment improved
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| Effect of sertraline therapy on alcohol abuse: in study conducted by speaker and colleagues, drinking declined
markedly among PTSD patients who received sertraline, although it increased in most severe cases
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| Study of prazosin in PTSD patients: subjects 10 Vietnam veterans who had failed treatment with other medications; received
10 mg prazosin or placebo; prazosin associated with decrease in CAPS score from 80 to 57 (placebo patients
worsened slightly); scores on sleep and nightmare evaluations also improved; effect sizes impressive
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| Risperidone: one study examined effect on 65 combat veterans with chronic PTSD, on multiple medications, and
participating in inpatient PTSD programs; effect size 0.6 (modest)
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| Acceptance and commitment therapy (ACT): aim to allow patients to experience disruptive feelings and memories
but still get on with their lives; patients make concrete plans for various domains of their lives, even while having troubling
thoughts (no effort made to squelch thoughts); consists of 20 weekly 90-min sessions; several clinical trials under way; preliminary
findings suggest some decrease in symptoms, but implications for patients’ ability to lead more normal lives unknown
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Educational Objectives
| The goal of this program is to review lessons learned and problems encountered in research on patients with treatment-
resistant depression and posttraumatic stress disorder (PTSD). After hearing and assimilating this program, the listener
will be able to:
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| 1. Identify risk factors for resistance in patients with depression.
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| 2. Advise depressed patients on how to obtain maximum treatment outcomes.
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| 3. Discuss some of the research comparing switching to augmenting various depression treatments.
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| 4. Explain the limitations of clinical trials on treating posttraumatic stress disorder (PTSD).
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| 5. Describe the limitations of effect size on studies of PTSD treatment.
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Discussed on this Program
Bopindolol malonate [Sandonorm] (not available in United States)
Bromocriptine mesylate [Parlodel, Parlodel Snap Tabs]
Bupropion HCl [Wellbutrin, Wellbutrin SR, Zyban]
Buspirone HCl [BuSpar]
Citalopram HBr [Celexa]
Desipramine HCl [Norpramin]
Fluoxetine HCl [Prozac, Prozac Pulvules, Prozac Weekly, Sarafem, Sarafem Pulvules]
Fluvoxamine maleate
Folic acid (folacin; pteroylglutamic acid; folate) [Folvite]
Imipramine HCl [Tofranil]
Lamotrigine [Lamictal, Lamictal Chewable Dispersible]
Liothyronine sodium (T3 ) [Cytomel, Triostat]
Liotrix (T4 and T3 ) [Thyrolar]
Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs]
Mirtazapine [Remeron, Remeron SolTab]
Modafinil [Provigil]
Nefazodone HCl [Serzone]
Nortriptyline HCl [Aventyl HCl, Aventyl HCl Pulvules, Pamelor]
Olanzapine [Zyprexa, Zyprexa Intramuscular, Zyprexa Zydis]
Paroxetine HCl [Paxil, Paxil CR, Pexeva]
Prazosin HCl [Minipress]
Risperidone [Risperdal, Risperdal Consta, Risperdal M-TAB]
Sertraline HCl [Zoloft]
Trazodone HCl [Desyrel, Desyrel Dividose]
Venlafaxine [Effexor, Effexor XR]
Suggested Reading
Alao AO et al: Pharmacological strategies in treatment-resistant depression. West Afr J Med 22(3):211, 2003; Frank
E et al: Efficacy of interpersonal psychotherapy as a maintenance treatment of recurrent depression. Contributing factors.
Arch Gen Psychiatry 49(5):401, 1992; Frank E et al: Interpersonal psychotherapy and antidepressant medication:
evaluation of sequential treatment strategy in women with recurrent major depression. J Clin Psychiatry 61(1):51,
2000; Grote NK and Frank E: Difficult-to-treat depression: the role of contexts and comorbidities. Biol Psychiatry
53(8):660, 2003; Hamner MB, Robert S, and Frueh BC: Treatment-resistant posttraumatic stress disorder: strategies
for intervention. CNS Spectr 9(10):740, 2004; Hinton DE et al: A randomized controlled trial of cognitive-behavior
therapy for Cambodian refugees with treatment-resistant PTSD and panic attacks: a cross-over design. J Trauma
Stress 18(6):617, 2005; Keller MB et al: A comparison of nefazodone, the cognitive behavioral-analysis system of
psychotherapy, and their combination in the treatment of chronic depression. N Engl J Med 342(20):1462, 2000; Keller
MB et al: Untangling depression and anxiety: clinical challenges. J Clin Psychiatry 66(11):1477, 2005; Keller MB:
Long-term treatment of recurrent and chronic depression. J Clin Psychotherapy 62 Suppl 24:3, 2001; Klein DN et al:
Cognitive-behavioral analysis system of psychotherapy as a maintenance treatment for chronic depression. J Consult
Clin Psychol 72(4):681, 2004; Kozaric-Kovacic D et al: Risperidone in psychotic combat-related posttraumatic
stress disorder: an open trial. J Clin Psychiatry 66(7):922, 2005; Labbate LA and Douglas S: Olanzapine for nightmares
and sleep disturbances in posttraumatic stress disorder (PTSD). Can J Psychiatry 45(7):667, 2000; Labbate LA
et al: Does comorbid anxiety or depression affect clinical outcomes in patients with post-traumatic stress disorder and
alcohol use disorders? Compr Psychiatry 45(4):304, 2004; Sajatovic M et al: Nefazodone therapy in patients with
treatment-resistant or treatment-intolerant depression and high psychiatric comorbidity. Clin Ther 21(4):733, 1999;
Schatzberg AF et al: Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the
other is not. Arch Gen Psychiatry 62(5):513, 2005; Thase ME et al: Treatment of major depression with psychotherapy
or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry 54(11):1009, 1997.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has
been disclosed: Dr. Dewan has received research grants from Eli Lilly and McNeil.
This program was recorded at the 32nd Annual Meeting on Treatment Resistant Disorders, held in San Francisco,
CA, from March 31-April 2, 2006, and sponsored by the University of Iowa College of Medicine and the American
Academy of Clinical Psychiatrists. The Audio-Digest Foundation thanks the speaker and the sponsors for their cooperation
in the production of this program.
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