The resistance to clozapine(Drug information on clozapine) is likely a consequence of the fact that it is a much more arduous treatment to implement for the physician and patient. There is fear of adverse effects, additional time and effort involved to get consent, and the need for appropriate medical monitoring. Patient resistance can often be overcome if the physician presents an appropriately positive assessment of this treatment option. Certainly, the evidence supporting clozapine versus alternative medications should be part of the discussion.
Make 1 medication change at a time, with adequate dose and duration of therapy. All guidelines and algorithms stress this. The studies of algorithm-driven treatment versus treatment as usual clearly show that organized, diligent, consistent, measurement-based care that gives adequate time for the medication to be dosed properly produces better and faster results than treatment as usual.12,13 Using this one-thing-at-a-time approach may be more important than using the specific drugs favored in the algorithms.
Managed care may be the chief source of opposition to this approach; daily changes in the pharmacotherapeutic regimen of inpatients are often demanded in order to justify "active" treatment. Approval of reimbursement for additional days in the hospital or outpatient visits may be withheld unless the physician complies. The other major opponent of the methodological approach is clinical experience, which often seems to support the various add-ons and premature switches. Patients often improve, or continue to improve, after these changes are made; however, placebo effect and the passage of time may explain much of this improvement.14
When there is no significant response to monotherapy, switch to a different agent rather than adding a second medication.Most physicians switch medications when the patient does not improve after a reasonable period. The key difficulty is in the evaluation of a partial but unsatisfactory response. How much of this partial response is due to the non-drug-related aspects of care? Has there in fact been no significant response to the medication itself? The Figure shows hypothetical data representative of the findings in hundreds of studies of different medications for mood and anxiety disorders.
With both active drug and placebo, patients show gradual improvement over 12 weeks but the active drug starts to separate from placebo after 2 weeks, and the effect size (difference from placebo) increases gradually over the 12 weeks; but the placebo also does moderately well at each time point. If a patient improves 20 or 25 points on this hypothetical rating scale by week 8 or week 12, this is a partial response, and most physicians (and patients) would attribute it to the active drug. However, a 20 to 25 point improvement is, in these hypothetical data, right at the mean of what is expected from placebo.
In clinical practice, there is no placebo but there are therapeutic elements, including the alliance and expectations set up by the diagnostic process, supportive follow-up meetings with the patient, and investigator bias (ie, the physician's belief and expectation that the medication will work). So, is this 20 to 25 point improvement a placebo effect? Active awareness of this issue, preparation of the patient for this possibility before treatment starts, and avoidance of premature drug add-ons before completing a full trial of a single agent could allow a more objective collaborative assessment of this question. It may prevent unnecessary polydrug therapy resulting from "augmentation" of placebo-related changes.
When initiating an SSRI, select an inexpensive generic for cost-effectiveness. The difference in acquisition costs among SSRIs is up to 60-fold in health care systems with bulk purchasing power, such as the Veterans Affairs Department (Table 3) and Medicaid programs. The least expensive choices right now are citalopram(Drug information on citalopram) and fluoxetine(Drug information on fluoxetine). Sertraline(Drug information on sertraline) has been available as a generic since July 1, 2006, but it is still very expensive, though its price is expected to come down. Many physicians have personal heuristics favoring the expensive SSRIs, probably resulting from biases induced by pharmaceutical company marketing. Patients may come to the office with their own preferences based on advertising, negative media coverage of certain products, and the recommendations of peers. However, the aggregate evidence suggests no significant differences in efficacy15,16 or adverse effects in adults, children/adolescents, or geriatric patients—although there may be more weight gain with paroxetine(Drug information on paroxetine).17 On the other hand, evidence does not support favoring paroxetine if insomnia is an initial symptom.18
Antidepressant procurement costs in the Department of Veterans Affairs (February 2007)*
|Antidepressant||Dose (mg)||Monthly cost ($)|
|Effexor SA (venlafaxine)||150||66.00|
*By law, these are the best prices available.