DRUG TREATMENT OF RES ISTANT
DEPRESSIONDR SUSHIL KUMAR S V,
MB BS, MD (PSYCHIATRY), MHA, FIPS, ASSISTANT PROFESSOR, DEPT.
OF PSYCHIATRYSS INSTITUTE OF MEDICAL
SCIENCES, DAVANGERE, INDIA
INTRODUCTION
• Degree of symptom reduction is related to functioning
• Partial responders with residual symptoms have a poorer prognosis compared to complete remitters
CATEGORIES OF RESPONSE• Response without remission (< 50% but > 25% from
baseline scores)• Non-response• Relapse (< 6 months of acute response)• Recurrences ( > 6 months)• Recovery (8 week period)• Breakthrough (Poop out)
CATEGORIES OF RESPONSE• Residual symptoms: irritability, social functioning,
dysfunctional attitudes, depressive cognitions
• Complete remission is the optimal goal (Trivedi &Kleiber, 2001)
• HAMD Score of < 7
DEFINITION OF TRD
• Failure to respond to 2 adequate trials of different chemical classes (Sourey et al, 1999)
• Several Staging Methods -- CPMP Guidelines -- Thase & Rush (1997) -- Massachusetts General Hospital
DEFINITION OF TRD
• Adequate dose & adequate duration
• Treatment intolerance (Schatzberg et al, 1983)
• 20% are treatment intolerant
FACTORS RELATED TO TRD• Patient and Treatment related factors
• Diagnosis -- Bipolarity -- Psychotic depression -- Atypical depression -- Co-morbid conditions
STRATEGIES FOR TRD
• Optimizing the dose• Augmentation• Combination • Switching
• No conclusive data identifies the optimal strategy (Nelson, 2003)
OPTIMIZING DOSE
• Most do not receive adequate trial (Keller et al, 1986; Dawson et al, 1999)
• Pseudo Resistant (Sackeim, 2001)
• Failure to use adequate dose for adequate duration have an iatrogenic effect in increasing resistance
OPTIMIZING DOSE
• Dose- 300 mg / day of imipramine
• SSRI- Flat dose response curve
• Duration- 4-6 weeks ; Extending to 10-12 weeks ( Nemeroff, 2001; Thase & Rush, 1995)
OPTIMIZING DOSE
• Structured Antidepressant Treatment History Form (Sackeim, 2001)
• Initial Choice of medication may depend on depressive symptoms
• Mirtazapine for insomnia; Venlafaxine for anxious depression (Meoni et al, 2004)
• Venlafaxine > SSRI
AUGMENTATION
• Adding an agent that is not a standard antidepressant
• Lithium (Joffe et al, 1993; Nierenberg et al, 2003)• Triiodothyronine (T3 > T4) (Joffe et al, 1993)
AUGMENTATION
• Mood Stabilizers ( Lamotrigine, Valproic acid, Carbamazepine)
• Pindolol (Nelson 2003; Fava 2001)
• Buspirone (Dimitriou & Dimitriou, 1998; Landen et al, 1998)
AUGMENTATION
• Atypical antipsychotics (Olanzapine, clozapine, Risperidone, Aripiprazole)
• Psychostimulants (Methylphenidate) (Thase & Rush, 1995)
• Lithium has been best studied
COMBINATION STRATEGIES• Combining one antidepressant with another
antidepressant
• SSRI+ Mirtazapine (de la Gandara et al, 2005)• SSRI+ Reboxetine ( Fava, 2001)• SSRI+ Bupropion (STAR٭D)• SSRI+ TCA (Nelson et al, 1991)
COMBINATION STRATEGIES• Venlafaxine + Bupropion (Keller, 2005)
• Fluoxetine + Olanzapine (Nemeroff, 2005)
• SSRI + Risperidone (Nemeroff, 2005)
• AD + Antipsychotic at 400 mg/ day ofCPZ
SWITCHING STRATEGIES• TCA ►TCA (Thase & Rush, 1995; Nierenberg et al, 1990;
Shelton, 1999)
• TCA ►Newer Heterocyclics (Thase & Rush,1995)
• TCA►SSRI (Thase & Rush, 1995)
SWITCHING STRATEGIES• SSRI►TCA (Fava, 2001)• SSRI►SNRI (Fava,2001, Poirier&Boyer,1999)• SSRI►Bupropion (Fava et al, 2003)• SSRI►SSRI (Zarate et al, 1996)• SSRI►MAOI (Thase & Rush, 1995)
SWITCHING STRATEGIES• SSRI→SNRI------- 30-60% (Poirier & Boyer, 1999)• SSRI→ SSRI------ 40-50% (Zarate et al, 1996)• TCA → SSRI------ 30-50% (Thase & Rush,1995)• TCA → TCA------- Poorer Response
ALGORITHM
• STAR٭D (Rush et al, 2003)
• Level 1- Citalopram
• Level 2- Switch to Bupropion, Sertraline, Venlafaxine Augment -Bupropion,Buspirone
ALGORITHM
• Level 3- Switch to Mirtazapine, TCA Augment- Lithium / T3
• Level 4- Switch to Tranylcypromine Augment- Mirtazapine + SNRI
ALGORITHM
• Level 1- SSRI• Level 2- SSRI or SNRI• Level 3- Augment with Bupropion, Lithium
• Treatment with MAOI or Lithium before ECT (Keller, 1995)
CONCLUSIONS
• Correct Diagnosis• Therapeutic Goal– Full Remission• Optimizing initial treatment• Augmenting and Combination strategies in
development• Factors resulting in TRD