Medication Treatment of Depression: Applications and Procedures

Acute-Treatment Phase
The treatment of depression has undergone considerable review, and consensus guidelines have been published. These work groups have attempted to arrive at a consensus based on previous research findings. From these guidelines an algorithm for decision making has been suggested for the acute-treatment phase, a modified version of which is presented in

Figure 39-3.

The tasks of the acute-treatment phase are to establish a diagnosis, define a short-term and long-term multidisciplinary treatment plan, select the most appropriate medication, titrate the dose to a therapeutic range, monitor side effects, and determine the magnitude and quality of response. This phase lasts from 6 to 12 weeks (see

Figure 39-1), and patients are usually seen every 1-2 weeks during this phase. If a satisfactory treatment response (discussed later in this section) is achieved, then the continuation phase will follow. If a new treatment is initiated, a second acute-treatment phase may ensue.

The acute-treatment phase begins with a clinical interview, diagnostic assessment, physical and neurological examination, and clinical and laboratory studies as appropriate. A decision to initiate treatment is based on the presence of diagnostic criteria for an MDE or a manic episode. The indications and contraindications for medication treatment are discussed in previous sections of this chapter.

A large number of factors can influence the choice of initial antidepressant drug; consequently, the decision regarding which agent to choose should be made on an individual basis. Most often the decision is based on choosing the safest drug with the side-effect profile most compatible with the specific symptoms that the patient has. Examples of this decision-making process would be the choice of an SSRI or bupropion in an overweight patient or the choice of a drug with prominent sedation in a patient with a long-standing history of insomnia.

The clinical factors that should be taken into account include primary diagnosis, subdiagnoses (e.g., presence of psychosis or atypical features), concomitant disorders and general health status, age, prior treatment history (including prior nonresponse to specific antidepressants), current severity of illness, and symptom profile. Certain subtypes of MDE have been associated with a greater likelihood of response to specific antidepressant drugs or combinations (

Table 39-9).

Dosage Titration
All current antidepressant and antimanic medications require an average of 10-21 days before improvement is clinically discernible. This time lag is unrelated to the time required to achieve therapeutic dosages and is thought to be due to a time-dependent process of neuronal adaptation. For most drugs, raising the dose beyond the usual therapeutic range does not speed up response but rather causes greater severity of side effects. For some drugs, doses higher than usual can be associated with a lower rate of response. These facts strongly argue for titrating to the usual therapeutic dosage range and patiently monitoring response for the first 21 days of treatment.

The rate of dosage titration for most antidepressant and antimanic drugs is closely related to the drug’s side-effect profile. The drugs with the most anticholinergic and antiadrenergic effects require the most careful titration. It is not uncommon to be unable to achieve therapeutic dosages of these medications because of the severity of the side effects. This is especially true for clomipramine, amitriptyline, doxepin, amoxapine, and trazodone. For all SSRIs except fluvoxamine, the therapeutic dosage may usually be started at once. Because of nausea and asthenia, most investigators have titrated the dosage of fluvoxamine over a 7- to 14-day period. The usual timing of medication administration and the time required to titrate dosages to therapeutic levels are listed in

Table 39-10.

Because of the low frequency and severity of side effects associated with SSRIs and the relative lack of routine clinical use of these agents, these medications are frequently used at dosages much higher than that required. This was common with fluoxetine in the first few years after its introduction, and gradually it became clear that 20 mg/day was adequate for most patients. Dosages of paroxetine and sertraline are often raised too rapidly. For these drugs, most investigators agree that dosages of 20 mg/day of paroxetine and 100-150 mg/day of sertraline are usually therapeutic.

Response Assessment
Assessment of treatment response should include an assessment of current depressive symptoms as well as an assessment of current level of functioning. Treatment response is clearly a continuous variable, with some patients having limited symptom relief, others having a complete restoration of normal functioning, and still others developing a degree of improvement that is better than their prior best level of functioning.

A group of experts in the field have developed conceptual guidelines for defining treatment response. These investigators have—as was done in DSM-III-R and DSM-IV—made the distinction between partial remission and full remission. Partial remission involves a treatment response such that the patient no longer meets the full criteria for an MDE or manic episode but continues to have more than minimal symptoms. Full remission would be declared when a patient no longer meets the criteria for MDE or manic episode and has no more than minimal symptoms. Factors important in assessing therapeutic response are listed in

Table 39-11.

If after 3-4 weeks the patient has not shown any evidence of response, the dosage should be titrated toward the maximum recommended dosage as tolerated. For TCAs and MAOIs the dosage can be increased at 3- to 4-day intervals, but for SSRIs it should be raised at 7- to 14-day intervals because most patients respond to the lower dose ranges. If after 4-6 weeks the patient still has not achieved a partial response, a careful reevaluation of the current treatment should be pursued. This involves discussing compliance with the patient, assessing the current dosage, and considering changing or augmenting the medication treatment.

If a partial response has been achieved after 4-6 weeks, waiting a full 12 weeks usually results in continued improvement and a full response. If after 12 weeks the rate of improvement has reached a plateau, consideration should be given to changing or augmenting medications. If improvement continues, the acute phase of treatment should be extended until the response has reached a plateau.

Drug Plasma Levels
Drug plasma levels are most important when the reasons for lack of response are being assessed, when a higher-than-expected degree of side effects is encountered, or when toxicity is suspected. Evidence supports the presence of minimum therapeutic plasma levels for desipramine, imipramine, and amitriptyline (above 150 ng/mL). For nortriptyline there appears to be a therapeutic window, with plasma levels below 50 ng/mL and above 150 ng/mL being less effective than those between. Plasma levels of desipramine, imipramine, and amitriptyline above 300 ng/mL are associated with higher risk of potentially dangerous side effects such as cardiac conduction abnormalities or seizures.