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