Focus on CME at the University of Université Manitoba Laval Down Again Strategies for Treating Refractory Depression By Guylain Bouchard, MD, MSc; and Nicole Thibodeau, MD, FRCPC Major depression is a devastating illness that affects a considerable number of people. Lifetime prevalence of depression in the general population is 17%. According to the National Comorbidity Survey, the prevalence of unipolar depression between the ages of 15 and 54 is 21.3% in women and 12.7% in men. 1 Major depression is not only a common condition, but also a recurring one. Results in a general outpatient context are striking, with 87% of patients experiencing a recurrence of their depression during the 15-year period the cohort was observed. 2 In a cohort (transverse section) of patients diagnosed with major depression, the condition had been developing for more than two years in approximately one-third of cases. 3 World Health Organization data estimate that major depression was the fourth leading cause of disability in 1990 and it is expected to rank second in 2020. In studies where various illnesses were compared with each other, it was discovered that the impact of depression on a person s daily functioning is comparable to that of advanced coronary disease. 4 The cost of physical care (excluding psychiatric care) for people with major depression is two to three times higher than In this article: 1.How serious is depression? 2.What are the neurobiologic concepts in depression today? 3.What are effective treatment strategies for refractory depression? Quick Facts on Depression Depression affects about 121 million people worldwide Depression can be reliably diagnosed and treated in primary care. At any given time, almost 3 million Canadians have serious depression, but less than 1/3 seek help. 20% of patients visiting primary care physicians have depressive symptoms; the condition of nearly half of these may go unrecognized. Find out more on page 42
Table 1 Systemic effects of depression Depression seems to not only create damage to the brain, there is a growing fear of it being a systemic disease that may promote: The deposit of fatty tissue Insulin resistance Bone resorption Increase in sympathetic tonus Coagulation Adapted from: Gold PW, Charney DS. Diseases of the mind and brain. Am J Psychiatry. 2002; 159 (11):1826. that of the general population. 1 The suicide rate among people with refractory depression is estimated at 15%. 3 These epidemiological studies convinced us that it would be pertinent to review current studies on depression, particularly when it becomes refractory. What happens neurobiologically? The prevalence of unipolar depression among 15 to 54 year-olds is 21.3% in women and 12.7% in men. The concordance rate between homozygote twins (50% to 55%) versus heterozygote twins (15%) indicates an inherited genetic predisposition to depression. 5 These genetic factors indicate the possible involvement of neurobiologic factors. Historically, the neurobiologic model of depression basically concentrated on a serotonin and norepinephrine deficit. 6 Recently, a more complex hypothesis involving neurotoxic effects related to the activation of the cortisol axis on the hippocampus has been suggested. 7 Depressive symptoms and cognitive problems seem to appear when hippocampal activity and frontal cortex metabolism are disturbed. It seems increasingly clear that serotoninergic and noradrenergic antidepressants slow the excessive activation of the cortisol axis by increasing the efficiency of glucocorticoid receptors in the hypothalamus (primary negative feedback). They also stimulate the activity of the hippocampus (including the induction of neuroprotective factors), which also tends to inhibit the release of corticotrophic releasing factor (CRF) by the hypothalamus. Activation of the cortisol axis, and the vicious circle of neurotoxicity with respect to the hippocampus, are thus reduced (Table 1). 8 All these data point to treatment objectives, such as obtaining a remission (75% improvement in symptoms) or, even better, complete remission. This is important because persistent symptoms of depression are a major predictor of relapse after one year. 9 What is refractory depression? Refractory depression is, unfortunately, a condition often seen by physicians. Following treatment with antidepressants, the chances of obtaining a partial therapeutic response are around 50% to 70%. Remission rates, however, are even lower, approximately 30% to 50% depending on the case series. There are varying definitions of refractory depression, making it difficult to compare studies on treatment efficacy. We have selected the following definition as our guide: Two unsuccessful trials with antidepressants administered at the appropriate dosage level (standard treatment dose) for a sufficiently long period (i.e., six weeks to eight weeks). 10 78 The Canadian Journal of CME / June 2003
Table 2 Factors that encourage optimization The following are factors that encourage optimization: Partial response to the antidepressant, without complete remission. Well-tolerated medication. Adapted from: Well KR, Katon W et al: Am J Psychiatry. 1994; 151: 694-700. What are the pharmacotherapy strategies? Before discussing these strategies, we should mention the following points: There is no universally recognized consensus. The guidelines are often more conservative than clinical practice. There are few controlled studies. Clinical practice often requires the use of strategies that have not yet been fully validated by controlled studies (particularly with regard to drug combinations). Table 3 Factors that favour substitution The following are factors that favour substitution: Absence of therapeutic response. Partial response, but the presence of unpleasant, persistent side-effects. Adapted from: Fredman SJ, Fava M, Kienke AS, et al: Partial response, non-response, and relapse on SSRIs in major depression: a survey of current next-step practices. J Clin Psychiatry 2000; 61: 403-7. There are four strategies to consider for your patients with refractory depression. 1. Optimization (increasing the dose) 2. Substitution (changing one medication for another) Following treatment with antidepressants, the chances of a partial therapeutic response are around 50% to 70%.
3. Combination (combined use of two antidepressants) 4. Potentiation (adding a non-antidepressant agent to an antidepressant) 1. Optimization This strategy is most commonly used in cases of partial response. For example, increasing fluoxetine from an initial 20 mg/day to a final dose of up to 40 mg/day to 80 mg/day has proved effective in increasing the number of patients who respond. 11 It should be noted that inadequate dosage is probably a common cause of treatment failure, given patients high rate of noncompliance with prescribed treatment (Table 2). 2. Substitution A survey of 400 U.S. psychiatrists has shown that the substitution of a different class of antidepressant is particularly popular in the management of patients with refractory depression (Table 3). Substitution by venlafaxine: Venlafaxine has been the subject of several studies in cases of non-response to a selective serotonin reuptake inhibitor (SSRI). Its efficacy has also been compared to SSRIs in randomized studies. Meta-analyses of these studies show favourable trends for venlafaxine. 12 The comparison of different medications always involves complex considerations, even if they only concern the selection of equivalent doses. Dr. Bouchard is professor, Université Laval, and psychiatrist, mood disorder clinic, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec. Dr. Thibodeau is professor, Université Laval, and director, mood disorder clinic, psychiatry department, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec. Remission rates after treatment with antidepressants are probably around 30% to 50% depending on the case series. Substitution by traditional MAOIs: Monoamineoxidase inhibitors (MAOIs), such as phenelzine and tranylcypromide, are still somewhat difficult to use. They require wash-out periods to eliminate the presence of the previous antidepressant (danger of serotoninergic syndrome, or hypertensive crisis). In addition, they cause orthostatic hypotension on a fairly frequent basis. Remember, however, that MAOIs are very useful agents and are often overlooked in circumstances where more commonly prescribed antidepressants and various combinations have failed. 3. Combinations Combining antidepressants is a strategy that is becoming increasingly popular today. It reflects a common clinical reality in the management of refractory depression, yet convincing data on combining antidepressants remain limited. Combining two SSRIs: This combination is rarely used. It is supported by a number of anecdotal cases. 13 This strategy can be effective when there is a comorbidity of depression and anxiety problems, including obsessive-compulsive problems. Such a combination, however, can increase the risk of serotoninergic sideeffects and syndromes. Combining an SSRI and nefazodone: Anecdotal reports suggest that this combination may be effective. It might even reduce certain SSRI side-effects. 80 The Canadian Journal of CME / June 2003
Table 4 Factors that favour potentiation The following are factors that could encourage the use of this strategy: Partial response to the antidepressant. Good tolerance of the antidepressant. There is an interaction with cytochrome P450 2D6 (paroxetine, fluoxetine), however, which may induce the production of a panic-causing metabolite (mcpp). Combining venlafaxine with an SSRI: No studies have been conducted on this combination yet. Only anecdotal reports indicate the combination s possible efficacy. There is, however, the risk of increasing serotoninergic side-effects and the risk of serotoninergic syndrome. 14 We should also remember that venlafaxine is a substrate of cytochrome P450 2D6. Combining mirtazapine with an SSRI: An openlabel study suggests this combination may be effective. 15 The combination of these antidepressants may have the advantage of reducing certain SSRI sideeffects (including sexual dysfunction). On the other hand, the combination also risks increasing sedation and weight gain. Combining bupropion with an SSRI: This combination has been the subject of four open-label studies. 16-19 It may reduce certain SSRI side-effects such as drowsiness. There is a risk of the combination accentuating anxiety or inducing tremor in some patients. Combining venlafaxine and bupropion: A recent open study evaluated this combination, which seemed to be effective. 20 The combination might be useful when symptoms of apathy and hypersomnia are present. The combination may cause a secondary increase in tremor and anxiety. It is a good idea to supervise the patient s blood pressure when using high doses of these medications. Increasing fluoxetine from an initial 20 mg/day to a final dose of up to 40-80 mg/day is effective.
Combining venlafaxine and mirtazapine: This clinical strategy is popular with psychiatrists. It seems to be well tolerated and clinically effective. A study is now underway, but has not yet been published. Combining desipramine (25 mg/day to 75 mg/day) and an SSRI: This combination has been studied the most so far. Several doubleblind studies have been conducted. The combination seems to provide faster action and A meta-analysis of five controlled studies estimates the risk of remaining depressed after adding lithium is 56% to 96% reduced. increased response rates in double-blind studies. 21 Despite the demonstrated benefits, high doses of tricyclics may cause a cardiotoxic effect because of drug interaction (cytochrome P450 2D6). Consequently, followup with blood tests and electrocardiogram is necessary. The decreased elimination of desipramine because of blockage by cytochrome P450 2D6 means treatment has to be initiated using smaller doses, slowly increasing thereafter. 4-Potentiation Table 4 presents the convincing data regarding potentiation. Adding lithium to an antidepressant: Lithium has been used as a potentiator since 1981 and this strategy has been studied extensively since that time. A meta-analysis of five controlled studies estimates that the risk of remaining depressed after the addition of lithium is 56% to 96% reduced. 22 Empirical data do not clearly identify the therapeutic dose and blood levels. Some authors recommend a starting dose of 600 mg/day (if there is no favourable response) to achieve plasma levels of around 0.8 meq/l to 1.0 meq/l. Adverse side-effects when using lithium as a potentiator are generally mild but hypothyroidism or renal failure may occur, hence the need for periodic laboratory testing. Adding thyroid hormones to the antidepressant: This strategy has mainly been studied with respect to tricyclic antidepressant potentiation in euthyroid patients. Triiodothyronine (T 3 ) has proven more effective than thyroxine (T 4 ). A double blind study has shown efficacy comparable to that of lithium. 23 The fact, however, remains that T 3 is rarely used today. The addition of an antipsychotic to an antidepressant: Adding a traditional antipsychotic has long been practised in the management of psychotic depression. Today, potentiation by an atypical antipsychotic is used in patients with major depression, even if no psychotic elements are present. Some symptoms, including severe insomnia, anxiety, severe distress, psychomotor retardation and/or agitation, are reasons for using this strategy. Studies have shown that olanzapine and risperidone enhance dopamine release in the prefrontal cortex. In addition, olanzapine (and risperidone to a lesser degree) increases the release of norepinephrine in the prefrontal cortex. 24 Moderate doses of an antipsychotic are recommended; either risperidone 0.5 mg/day to 2 mg/day, or olanzapine 5 mg/day to 20 mg/day. The addition of an atypical antipsychotic appears promising in the management of refrac- 82 The Canadian Journal of CME / June 2003
tory depression. Further studies are awaited in order to have a better idea of the effects of such potentiation. Certain disadvantages (e.g., weight gain, or possible extrapyramidal reactions) mean that this strategy is reserved for particular clinical situations or cases that are treatment-resistant. Dopaminergic agonists: Dopamine seems to play a role in both the development and management of depression. However, the addition of a dopaminergic medication such as pramipexole, 25 amantadine, or pergolide, has not yet been the subject of controlled studies. Psychostimulants: The use of psychostimulants, such as methylphenidate, dextroamphetamine and pemoline, has been evaluated in open-label studies, which seem to indicate that these agents are effective. 26 This strategy would appear to have the advantage of rapid onset. However, it is possible that efficacy wanes over time. In addition, the potentiation may increase anxiety and irritability. Potential abuse by certain vulnerable patients should also be taken into consideration. Modafinil: This medication is used to treat hypersomnia and narcolepsy. It has been identified as a possible adjuvant in the treatment of refractory depression. Its efficacy has been suggested, but there is little proof available at the moment. 27 Anticonvulsants: The addition of anticonvulsants, such as valproic acid, carbamazepine, lamotrigine, gabapentin, and topiramate, may help manage irritability, anxiety and insomnia, but the sole evidence of this is several anecdotal reports. Other potentiators: Potentiators such as inositol, estrogens, opiates, pindolol, and folic acid are mentioned in medical literature, but further studies are required. Buspirone: Buspirone is without doubt one of the molecules whose efficacy is the most controversial in the treatment of refractary depression. The only controlled study that exists reports a response to buspirone of around 51% versus placebo 47%. 28 Take-home message What is refractory depression? Refractory depression is defined as: two unsuccessful trials with antidepressants administered at the appropriate dosage level (standard treatment dose) for a sufficiently long period (i.e., six weeks to eight weeks). What are the strategies? 1. Optimization (increasing the dose) 2. Substitution (changing one medication for another) 3. Combination (combined use of two antidepressants) 4. Potentiation (adding a non-antidepressant agent to an antidepressant) What now? Refractory depression is one of the most serious illnesses of our time. For the clinician, its management represents a major therapeutic challenge. A better knowledge of the treatments available, their efficacy, side-effects and indications is useful. At a time when we are learning more and more about the neurobiological mechanisms involved in depression, and new drugs are becoming available to us, we can increasingly look for remission in our patients. CME Continued on page 86. The Canadian Journal of CME / June 2003 83
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