Dr Ayedh

REFRACTORY DEPRESSION

Facts
MDD has about 20% lifetime risk the most disabling condition for females two-thirds of all depressed patients are

female the second most disabling condition in developed countries the fourth most disabling condition worldwide associated with increases in both medical and psychiatric morbidity and mortality rates

Definition of TRD
major depression that is not secondary to a

medical or drug-induced condition and that has failed to respond, or to sustain response, to an adequate trial of a standard antidepressant.

Difficulty Defining Refractory Depression

what does it mean to fail to respond? how much residual depression is required to

define refractoriness? What dose and what duration of drug therapy are required to be considered adequate?

Factors Contributing to Nonresponse

A.Clinical: 1.Noncompliance:

intolerable side effects limited information about medication poor attitude toward drug therapy family resistance high cost of drugs

 Improve compliance by: Careful preparation of the patient and family frank discussion about side effects simplifying drug schedules Checking plasma levels

Cont. Factors Contributing to Nonresponse

2. presence of personality disorder 3. prior treatment failure 4.near delusional status 5. age 35 or younger at hospitalization 6. duration of depressive episode 7. recurrence of the index episode 8. dysthymia, and secondary depression
Nelson and colleagues

Cont.
B. Comorbid Medical Conditions: C.Common Comorbid Psychiatric

Conditions

Monotherapy Treatment Approaches

Tricyclic-to-Alternative Antidepressant low rates of response, 9%and 30% to another tricyclic 56% response to Trazodone 62% positive response to a subsequent trial of MAOI 43% to 75% to SSRI
Thase and Rush, + sm open label studies

 SSRI-to-Alternative Antidepressant

73% paroxetine nonresponders improved with 6-week trial of imipramine * 91% pts intolerant to fluoxetine complete on sertraline 50mg/day+

*Peselow and associates

+Brown and Harrison

 High-Dose Monotherapies subtherapeutic plasma levels on standard doses in sm pts

#41 pts who failed 2 respond to 8 wks of fluoxetine 20mg/day randomly assigned: fluoxetine 40 -60mg/d fluoxetine 20/d+ desipramine 25-50mg/d fluoxetine 20mg/d + lithium 300-600mg/d showed the greatest reduction in the high-dose grps (mean 14.1 to 7.3) compared with fluoxetine + desipramine (16.1 to 13.9) or fluoxetine + lithium (13.6 to 10.6)
#Fava and colleagues

 Venlafaxine

mixed NA and 5HT uptake activity * an open trial conducted of venlafaxine in 84 outpts and inpts with refractory MDD , defined as: failure of at least 3 adequate trials of A/D from at least 2 different A/D classes or ECT, + at least 1 attempt at augmentation. Abt 1/3 of pts had partial or full response, and 46% of the responders sustained the response

*Nierenberg and associates

Combination/Augmentation Therapy
Lithium Augmentation of Tricyclics Lithium Augmentation of SSRIs Thyroid Hormone Augmentation Heterocyclic-SSRI Combination Tricyclic-MAOI Combinations Antidepressant-Anticonvulsant

Combinations

 Other Therapy Combinations

most studies:SSRI or Tricyclics +: psychostimulants such as dextroamphetamine or methylphenidate estrogen supplementation buspirone augmentation

Cont.
Antipsychotics Electroconvulsive Therapy Psychotherapy

Novel interventions
*Transcranial magnetic stimulation (TMS) effective in the treatment of antidepressant

resistant major depression significantly improve patients' quality of life (QoL) and functional status Noninvasive Option Early Response No Systemic Exposure

*multicenter, community-based study by The NeuroStar (Neuronetics, Malvern, Pennsylvania)

 Low-Dose Ketamine

+ 6 low-dose (.5 mg/kg) i.v.infusions of ketamine administered 3 times a week over the 2 weeks then monitored for up to 3 months or until a relapse 70.8% had a reduction of 50% or > in MADRS score at the study's endpoint
+study by Dr. Murrough and colleagues published in Clinical Pharmacology and Therapeutics

Deep Brain Stimulation

:

distinct advantage of being reversible, nonablative, and modulatory Nucleus Accumbens and Ventral Striatum Subgenual Cingulate Cortex: Area 25 Inferior Thalamic Peduncle Rostral Cingulate Cortex: Area 24a Lateral Habenula

Surgery
Almost obsolete Ablative and irreversible stereotactic limbic leukotomy anterior capsulotomy anterior cingulotomy