Another issue is whether to cross-taper, that is, to lower the dose of the first agent while titrating up the next, or to discontinue the first before the second. When catastrophic drug interactions would result from overlap, such as the switch from an SSRI to a monoamine oxidase (MAO) inhibitor, a suitable wash-out period is necessary. This can also occur if the first antidepressant is believed to cause intolerable side effects.
In most other instances where no absolute contraindications exist, cross-tapering may be worthwhile despite theoretical risks such as serotonin syndrome when overlapping an SSRI and venlafaxine. Cross-tapering helps reduce the risk of side effects associated with abrupt discontinuation including nausea, myalgias, headache, and dysphoria, and may minimize the loss of antidepressant benefit from the initial agent before the impact of the second agent is realized.
Great hope for new knowledge with STAR*D
In recognition of the substantial direct and indirect costs, the morbidity and mortality associated with unremitted depression, and the considerable gaps in knowledge about optimal management at key decision points, the National Institute of Mental Health (NIMH) has launched the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This is a multisite, multistep, prospective, randomized clinical trial of nonpsychotic major depressive disorder.21
STAR*D: A NOVEL DESIGN PERMITTING INPUT FROM CLINICIAN AND PATIENT
STAR*D represents an initiative unique in the history of depression trials. Its novel “equipoise stratified” design26 is a hybrid between strict randomization to treatments without input from patients or clinicians (completely randomized designs) and a form of randomization in which subjects are assigned only to overarching strategies within which the particular treatments are determined by the clinician (clinician’s choice designs).
In STAR*D, a patient is asked at each level to define with his or her clinician all treatments that would be equally acceptable, based on a preference for certain potential side effects over others, interest in psychotherapy, or desire to retain a medication to which the patient has responded at least partially.
To be eligible to continue, however, the patient must agree to be randomized across at least some of the options testing some of the key hypotheses. For example, a participant at Level 2 who specifically wished to pursue cognitive therapy could not do that alone, but could agree to randomization to cognitive therapy with or without citalopram.
The study seeks to balance the goal of recruiting and retaining a broadly representative cross-section of patients—many of whom would reasonably expect to have some say about their treatment with their prescribing clinician—with the goal of providing statistically rigorous, randomization-based inferences upon which meaningful treatment guidelines can be based.
Approximately 4,000 adult depressed outpatients without an established history of antidepressant resistance will be recruited across the country. In contrast to efficacy trials, this effectiveness trial is meant to more closely parallel real-world practice (Box 2).
Patients will be treated initially with citalopram for 12 weeks (Level 1), with general guidelines for titration based upon response and tolerability. It is anticipated that about 2,000 individuals will exhibit unremitting depression despite SSRI treatment and/or intolerance to the SSRI and will be eligible for randomization to subsequent “switching” or “augmentation” strategies; this forms the core of the study across 3 successive levels.
Level 2 randomized treatments include four distinctive switching options—sertraline, bupropion, venlafaxine, or cognitive therapy—as well as 3 augmentation options—citalopram plus bupropion, buspirone, or cognitive therapy.
Those whose depression fails to remit will be eligible for randomization at Level 3 to different switching options—mirtazapine vs. nortripyline, or augmentation options—lithium or thyroid—added to the primary Level 2 antidepressant.
Finally, at Level 4, patients who continue to have unremitted depression despite successive treatments will be eligible for random assignment to 1 of 2 switching options—tranylcypromine vs. the combination of mirtazapine and venlafaxine.
Two new somatic treatments
Repetitive Transcranial Magnetic Stimulation (rTMS) rTMS is used to induce electrical current in the brain without causing seizures. Using a rapidly alternating current with a hand-held electromagnet that generates about 2 tesla will, in turn, induce or interrupt current (depolarization) in cortical interneurons about 2 cm below the surface of the skull. rTMS delivers energy without the impedance of the skull and is thought to be excitatory at high frequencies (20 Hz) and inhibitory at lower frequencies (5 to 10 Hz). This theory remains to be rigorously tested.22
Overall, the clinical effects reported in early studies on rTMS have been modest at best, while later studies have found either no difference from placebo or a robust effect. rTMS is a potential therapeutic tool not yet ready for widespread clinical use.22