DIAGNOSTIC AND THERAPEUTIC ADVANCES
TREATMENT RESISTANT MOOD DISORDERS
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
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
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.