Treatment resistance poses a serious clinical dilemma to the psychiatrist and may result in prolonged and serious functional limitation for the patient including major morbidity and mortality consequences. When there is minimal response to standard treatment with anti-depressants, psychotherapy, and supportive interventions despite several modifications in treatment approach and a trial of sufficient length, a systematic analysis becomes imperative to break through the stalemate.

Thirty percent of depressed patients fail to respond and up to sixty percent have insufficient improvement of clinical indices at recovery. Obvious initial considerations involve a re-assessment of the diagnosis (uni-polar, bi-polar, atypical, rapid cycling, seasonal), medication dosage, patient compliance with treatment, and the presence of co-morbid psychiatric and medical disorders (including substance abuse, cognitive disorders, endocrine and oncologic disorders).

Although brain imaging procedures are not definitive diagnostic or predictive tools for treatment resistance, they have great promise for understanding structural and neurochemical abnormalities which may define an individualized treatment plan for specific patients. For example, a study using hexamethylpropylene amine oxime (HMPAO , currently referred to as exametazime) SPECT (single photon emitted computed tomography), exhibited increased activity in the hippocampus and amygdala in treatment resistant patients, which would imply that the limbic system plays an important role in mediating treatment refractoriness.

Gender, genetic, and age characteristics may contribute to mood disorder subtypes (psychosis, catatonia, pseudo-dementia, and severe vegetative signs) requiring specialized intervention. Special pharmacokinetic issues such as, medication absorption, interaction and plasma drug concentration should be considered since there can be as much as a thirty fold range of drug metabolic differences among patients.

Numerous augmentation strategies have been proposed to combine anti-depressants with (1) Mood Stabilizing Agents : Lithium, Anti-Convulsants (Valproic Acid, Carbamazepine,Lamotrigine); Calcium Channel Blockers: Verapamil, Nimodipine, Isradipine. (2) Receptor Agonist-Antagonists: Buspirone, Pindolol. (3) Neurotransmitter Enhancement: Fenflouramine, NSRI's (Venlafaxine, Nefazodone), SSRI-TCA, MAOI-TCA. (4) Thyroid Hormone. Dose level and length of trial augmentation may be crucial variables in determining therapeutic effect. When utilizing thyroid augmentation, a baseline thyroid assessment should be made (including extra-sensitive TSH and TRH-TSH when indicated). T3 may be more effective then T4 for augmentation, but caution should be exercised in length of use to avoid inducing hypothyroidism.

Innovative treatment approaches to augmentation utilizing unique neurobiologic pathways include: (1) Cortisol Synthesis Inhibitors: ketoconazole, metyrapone. (2) Selective and Reversible MAO Agents: selegiline, moclobemide (3) Serotonin-Dopamine Blocking Agents: clozapine.

ECT remains a solid alternative both in the sequence of treatment decisions and for primary intervention in selected situations of severe suicidal potential or deteriorating physical health demanding rapid reversal. More recent innovative approaches through brain area-specific electro-magnetic radiation may hold promise in the most severely resistant patients.

Special psychosocial and trauma-inducing factors may influence the course of affective illness including bereavement, loss and separation, status devaluation, learned helplessness, immigration and displacement, and natural disaster. The neurobiologic response characteristics of psychologic stress and trauma may augment, prolong, and have a deteriorating impact on a concurrent mood disorder. With chronicity of illness, actual CNS structural damage and problematic kindling of mood disregulation may lead to a further deterioration.

Thoughtful analysis and vigorous response to treatment resistant mood disorder is imperative not only to bring about clinical improvement, but to establish a firm groundwork for the most crucial phase of treatment to come- prevention of relapse.