Depression Treatment Wichita KS

Excerpt from "Mental Health:  A Report of the Surgeon General"

Treatment of Major Depressive Episodes

Pharmacotherapies
Antidepressant medications are effective across the full range of severity of major depressive episodes in major depressive disorder and bipolar disorder (American Psychiatric Association, 1993; Depression Guideline Panel, 1993; Frank et al., 1993). The degree of effectiveness, however, varies according to the intensity of the depressive episode. With mild depressive episodes, the overall response rate is about 70 percent, including a placebo rate of about 60 percent (Thase & Howland, 1995). With severe depressive episodes, the overall response rate is much lower, as is the placebo rate. For example, with psychotic depression, the overall response rate to any one drug is only about 20 to 40 percent (Spiker, 1985), including a placebo response rate of less than 10 percent (Spiker & Kupfer, 1988; Schatzberg & Rothschild, 1992). Psychotic depression is treated with either an antidepressant/antipsychotic combination or ECT (Spiker, 1985; Schatzberg & Rothschild, 1992).

There are four major classes of antidepressant medications. The tricyclic and heterocyclic antidepressants (TCAs and HCAs) are named for their chemical structure. The MAOIs and SSRIs are classified by their initial neurochemical effects. In general, MAOIs and SSRIs increase the level of a target neurotransmitter by two distinct mechanisms. But, as discussed below, these classes of medications have many other effects. They also have some differential effects depending on the race or ethnicity of the patient.

The mode of action of antidepressants is complex and only partly understood. Put simply, most antidepressants are designed to heighten the level of a target neurotransmitter at the neuronal synapse. This can be accomplished by one or more of the following therapeutic actions: boosting the neurotransmitter’s synthesis, blocking its degradation, preventing its reuptake from the synapse into the presynaptic neuron, or mimicking its binding to postsynaptic receptors. To make matters more complicated, many antidepressant drugs affect more than one neurotransmitter. Explaining how any one drug alleviates depression probably entails multiple therapeutic actions, direct and indirect, on more than one neurotransmitter system (Feighner, 1999).

Selection of a particular antidepressant for a particular patient depends upon the patient’s past treatment history, the likelihood of side effects, safety in overdose, and expense (Depression Guideline Panel, 1993). A vast majority of U.S. psychiatrists favor the SSRIs as“first-line” medications (Olfson & Klerman, 1993). These agents are viewed more favorably than the TCAs because of their ease of use, more manageable side effects, and safety in overdose (Kapur et al., 1992; Preskorn & Burke, 1992). Perhaps the major drawback of the SSRIs is their expense: they are only available as name brands (until 2002 when they begin to come off patent). At minimum, SSRI therapy costs about $80 per month (Burke et al., 1994), and patients taking higher doses face proportionally greater costs.

Four SSRIs have been approved by the FDA for treatment of depression: fluoxetine, sertraline, paroxetine, and citalopram. A fifth SSRI, fluvoxamine, is approved for treatment of obsessive-compulsive disorder, yet is used off-label for depression.¹¹ There are few compelling reasons to pick one SSRI over another for treatment of uncomplicated major depression, because they are more similar than different (Aguglia et al., 1993; Schone & Ludwig, 1993; Tignol, 1993; Preskorn, 1995). There are, however, several distinguishing pharmacokinetic differences between SSRIs, including elimination half-life (the time it takes for the plasma level of the drug to decrease 50 percent from steady-state), propensity for drug-drug interactions (e.g., via inhibition of hepatic enzymes), and antidepressant activity of metabolite(s) (DeVane, 1992). In general, SSRIs are more likely to be metabolized more slowly by African Americans and Asians, resulting in higher blood levels (Lin et al., 1997).

The SSRIs as a class of drugs have their own class-specific side effects, including nausea, diarrhea, headache, tremor, daytime sedation, failure to achieve orgasm, nervousness, and insomnia. Attrition from acute phase therapy because of side effects is typically 10 to 20 percent (Preskorn & Burke, 1992). The incidence of treatment-related suicidal thoughts for the SSRIs is low and comparable to the rate observed for other antidepressants (Beasley et al., 1991; Fava & Rosenbaum, 1991), despite reports to the contrary (Breggin & Breggin, 1994).

Some concern persists that the SSRIs are less effective than the TCAs for treatment of severe depressions, including melancholic and psychotic subtypes (Potter et al., 1991; Nelson, 1994). Yet there is no definitive answer (Danish University Anti-depressant Group, 1986, 1990; Pande & Sayler, 1993; Roose et al., 1994; Stuppaeck et al., 1994).

Side effects and potential lethality in overdose are the major drawbacks of the TCAs. An overdose of as little as 7-day supply of a TCA can result in potentially fatal cardiac arrhythmias (Kapur et al., 1992). TCA treatment is typically initiated at lower dosages and titrated upward with careful attention to response and side effects. Doses for African Americans and Asians should be monitored more closely, because their slower metabolism of TCAs can lead to higher blood concentrations (Lin et al., 1997). Similarly, studies also suggest that there may be gender differences in drug metabolism and that plasma levels may change over the course of the menstrual cycle (Blumenthal, 1994b).

In addition to the four major classes of antidepressants are bupropion, which is discussed below, and three newer FDA-approved antidepressants that have mixed or compound synaptic effects. Venlafaxine, the first of these newer antidepressants, inhibits reuptake of both serotonin and, at higher doses, norepinephrine. In contrast to the TCAs, venlafaxine has somewhat milder side effects (Bolden-Watson & Richelson, 1993), which are like those of the SSRIs. Venlafaxine also has a low risk of cardiotoxicity and, although experience is limited, it appears to be less toxic than the others in overdose. Venlafaxine has shown promise in treatment of severe (Guelfi et al., 1995) or refractory (Nierenberg et al., 1994) depressive states and is superior to fluoxetine in one inpatient study (Clerc et al., 1994). Venlafaxine also occasionally causes increased blood pressure, and this can be a particular concern at higher doses (Thase, 1998).

Nefazodone, the second newer antidepressant, is unique in terms of both structure and neurochemical effects (Taylor et al., 1995). In contrast to the SSRIs, nefazodone improves sleep efficiency (Armitage et al., 1994). Its side effect profile is comparable to the other newer antidepressants, but it has the advantage of a lower rate of sexual side effects (Preskorn, 1995). The more recently FDA-approved antidepressant, mirtazapine, blocks two types of serotonin receptors, the 5-HT_² and 5-HT_³ receptors (Feighner, 1999). Mirtazapine is also a potent antihistamine and tends to be more sedating than most other newer antidepressants. Weight gain can be another troublesome side effect.

Figure 4-2 presents summary findings on newer pharmacotherapies from a recent review of the treatment of depression by the Agency for Healthcare Research and Quality (AHRQ, 1999). There have been few studies of gender differences in clinical response to treatments for depression. A recent report (Kornstein et al., in press) found women with chronic depression to respond better to a SSRI than a tricyclic, yet the opposite for men. This effect was primarily in premenopausal women. The AHRQ report (1999) also noted that there were almost no data to address the efficacy of pharmacotherapies in post partum or pregnant women.

Alternate Pharmacotherapies
Regardless of the initial choice of pharmacotherapy, about 30 to 50 percent of patients do not respond to the initial medication. It has not been established firmly whether patients who respond poorly to one class of antidepressants should be switched automatically to an alternate class (Thase & Rush, 1997). Several studies have examined the efficacy of the TCAs and SSRIs when used in sequence (Peselow et al., 1989; Beasley et al., 1990). Approximately 30 to 50 percent of those not responsive to one class will respond to the other (Thase & Rush, 1997).

Among other types of antidepressants, the MAOIs and bupropion are important alternatives for SSRI and TCA nonresponders (Thase & Rush, 1995). These agents also may be relatively more effective than TCAs or SSRIs for treatment of depressions characterized by atypical or reversed vegetative symptoms (Goodnick & Extein, 1989; Quitkin et al., 1993b; Thase et al., 1995). Bupropion and the MAOIs also are good choices to treat bipolar depression (Himmelhoch et al., 1991; Thase et al., 1992; Sachs et al., 1994). Bupropion also has the advantage of a low rate of sexual side effects (Gardner & Johnston, 1985; Walker et al., 1993).

Bupropion’s efficacy and overall side effect profile might justify its first-line use for all types of depression (e.g., Kiev et al., 1994). Furthermore, bupropion has a novel neurochemical profile in terms of effects on dopamine and norepinephrine (Ascher et al., 1995). However, worries about an increased risk of seizures delayed bupropion’s introduction to the U.S. market by more than 5 years (Davidson, 1989). Although clearly effective for a broad range of depressions, use of the MAOIs has been limited for decades by concerns that when taken with certain foods containing the chemical tyramine (for example, some aged cheeses and red wines); these medications may cause a potentially lethal hypertensive reaction (Thase et al., 1995). There has been continued interest in development of safer, selective and reversible MAOIs.

Hypericum (St. John's Wort). The widespread publicity and use of the botanical product from the yellow-flowering Hypericum perforatum plant with or without medical supervision is well ahead of the science database supporting the effectiveness of this putative antidepressant. Controlled trials, mainly in Germany, have been positive in mild-to-moderate depression, with only mild gastrointestinal side effects reported (Linde et al., 1996). However, most of those studies were methodologically flawed, in areas including diagnosis (more similar to adjustment disorder with depressed mood than major depression), length of trial (often an inadequate 4 weeks), and either lack of placebo control or unusually low or high placebo response rates (Salzman, 1998).

Post-marketing surveillance in Germany, which found few adverse effects of Hypericum, depended upon spontaneous reporting of side effects by patients, an approach that would not be considered acceptable in this country (Deltito & Beyer, 1998). In clinical use, the most commonly encountered adverse effect noted appears to be sensitivity to sunlight.

Figure 4-2. Treatment of depression-newer pharmacotherapies: Summary findings

Basic questions about mechanism of action and even the optimal formulation of a pharmaceutical product from the plant remain; dosage in the randomized German trials varied by sixfold (Linde et al., 1996). Several pharmacologically active components of St. John's wort, including hypericin, have been identified (Nathan, 1999); although their long half-lives in theory should permit once daily dosing, in practice a schedule of 300 mg three times a day is most commonly used. While initial speculation about significant MAO-inhibiting properties of hypericum have been largely discounted, possible serotonergic mechanisms suggest that combining this agent with an SSRI or other serotonergic antidepressant should be approached with caution. However, data regarding safety of hypericum in preclinical models or clinical samples are few (Nathan, 1999). At least two placebo-controlled trials in the United States are under way to compare the efficacy of Hypericum with that of an SSRI.

Augmentation Strategies
The transition from one antidepressant to another is time consuming, and patients sometimes feel worse in the process (Thase & Rush, 1997). Many clinicians bypass these problems by using a second medication to augment an ineffective antidepressant. The best studied strategies of this type are lithium augmentation, thyroid augmentation, and TCA-SSRI combinations (Nierenberg & White, 1990; Thase & Rush, 1997; Crismon et al., 1999).

Increasingly, clinicians are adding a noradrenergic TCA to an ineffective SSRI or vice versa. In an earlier era, such polypharmacy (the prescription of multiple drugs at the same time) was frowned upon. Thus far, the evidence supporting TCA-SSRI combinations is not conclusive (Thase & Rush, 1995). Caution is needed when using these agents in combination because SSRIs inhibit metabolism of several TCAs, resulting in a substantial increase in blood levels and toxicity or other adverse side effects from TCAs (Preskorn & Burke, 1992).

(Source: The information is exerpted from the Surgeon General's report that pertains specifically to pharmacotherapy for major depression.   Click here to read the entire section of the report at the Surgeon General's site and to see the references.)