Combination therapies in antidepressive drug refractory depression--an overview

Despite the availability of a wide range of effective antidepressant drugs, nearly 30% of depressed patients fail to respond to antidepressant treatment. Various pharmacological strategies have been developed to treat such refractory depression, of which augmentation therapies are one of the most important. This article reviews both benefits and risks of all known augmentation therapies. Among these treatment strategies the efficacy of lithium augmentation is very well documented by a large number of controlled studies - lithium augmentation can therefore be recommended in depression refractory to antidepressant treatment. The efficacy of triiodothyronine (T3) augmentation and the combination of different antidepressants - like a TCA-MAOI combination - is described in a large number of case reports and uncontrolled studies; the number of placebo controlled double blind studies, confirming the efficacy of these treatment strategies, is however relatively small. T3 augmentation and combined antidepressant treatment may therefore be considered in the treatment of refractory depression; in contrast to lithium augmentation these combination therapies are however only second-line strategies. Other augmentation therapies (TCA + stimulants, TCA + reserpine, TCA + yohimbine, TCA + fenfluramine, SSRI + buspirone) are very interesting clinical research strategies, but don't have too much importance in clinical practice at the moment.     

Monocyte-endothelial cell interactions in vitro, with reference to the influence of interleukin-1 and tumor necrosis factor

This review discusses augmentation strategies for patients with obsessive-compulsive disorder who fail to respond to treatment. A patient's failure to respond to treatment may be due to any of a number of factors, such as noncompliance with a behavioral program, concurrent severe depression or personality disorder, certain ritualistic behaviors, inaccurate diagnosis, and inadequate treatment. It is particularly important that comorbid psychiatric disorders be diagnosed and treated. A review of the literature and my experience with the use of augmenting agents such as lithium, buspirone, clonidine, fenfluramine, antidepressants, anxiolytic agents, and neuroleptics in treatment-resistant obsessive-compulsive disorder are presented. Existing evidence suggests that some of these approaches are useful for some patients. However, many questions remain, and much research remains to be done on this topic.     

Pathology of MEN-1: morphology, clinicopathologic correlations and tumour development

Augmentation therapy is used for those situations where a patient's depression is either treatment-resistant, or partially and/or insufficiently responsive to treatment. It also may be used to attempt to induce a more rapid treatment response. Using drugs together may increase the risk of adverse effects, through potentiation of existing adverse effects or alterations in plasma concentrations of the drug. It is important that clinicians are aware of potential risks of augmentation therapy. Lithium augmentation of a tricyclic antidepressant is relatively well tolerated and the dangers are no greater than using these medications on their own. There are also no reports of serious adverse events when lithium is added to a monoamine oxidase inhibitor. With lithium augmentation of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) therapy there have been case reports of the development of a central serotonin syndrome, and thus caution must exercised. A serious concern when using a tricyclic antidepressant to augment an SSRI is the effect of the SSRI on the cytochrome P450 system and the resulting significant increase in tricyclic antidepressant blood concentrations. Augmentation with thyroid hormones appears to be well tolerated and effective. Case reports and open studies indicate that augmentation with buspirone and the psychostimulants, carbamazepine and valproic acid (valproate sodium) is effective and results in minimal adverse effects. However, there is no empirical evidence supporting these results. Recent work supports the tolerability and efficacy of pindolol augmentation. Considerable caution should be exercised when combining psychotropic drugs. The practitioner should only do so with a full knowledge of the compounds involved and their pharmacological properties.     

Psychotherapy of refractory depressions

Psychotherapy is a potentially valuable intervention for treatment-resistant depression. This review provides a brief, general overview of the use of psychotherapy to treat depression and more focused consideration of time-limited interpersonal, behavioral, and cognitive behavioral strategies for patients who are not responsive to antidepressant medication. Effective strategies emphasize individualized assessment, psychoeducation, a high level of structure and therapist activity, operationalized short-term goals, self-help and homework activities, and an empirical-collaborative approach to treatment. Although some treatment-resistant patients respond to therapy alone, more promising evidence is emerging from studies of combined strategies.     

A review of the use of augmentation therapy for the treatment of resistant depression: implications for the clinician

OBJECTIVE: To critically review the literature on augmentation therapy in resistant depression in order to assist the clinician to make a reasoned choice. Augmentation therapy is defined as the addition of a second agent to an existing antidepressant regimen with the aim of achieving improved clinical response. METHOD: The available literature which related specifically to currently popular augmentation strategies in treatment resistant depression for the past 20 years was examined. The scientific evidence supporting the efficacy of these regimens and their safety was reviewed. RESULTS: Considerable research on lithium augmentation has been undertaken, and on triiodothyronine augmentation to a lesser degree. A number of other drugs have been trialed as augmentation agents with claims of success; however, most of the evidence supporting these agents is anecdotal and in the form of case reports. There are very few well-performed double-blind placebo-controlled studies of augmentation therapy. CONCLUSIONS: Because of possible complex pharmacodynamic and pharmacokinetic interactions, augmentation therapy is not without its potential complications. Lithium augmentation of tricyclic antidepressants can be recommended as a safe and effective strategy and there is a body of scientific evidence supporting the addition of T3 as an effective augmentation agent. Recent research with pindolol augmentation of selective serotonin re-uptake inhibitors (SSRIs) is encouraging, but these findings require replication. There is no empirical evidence supporting buspirone, carbamazepine, sodium valproate, methylphenidate or amphetamine as effective augmentation agents, or that adding a tricyclic to a SSRI has usefulness in relieving depressive symptoms. There is a need for considerable research in this area, with more prospective well-controlled placebo studies.     

Raising questions about antidepressants

Antidepressant medication has apparently become the most popular treatment for depression in the USA. Several beliefs about the efficacy of antidepressant medications prevail among mental health professionals and the public. This paper explores relevant research data and raises questions about these beliefs. Many of the common beliefs about these medications are not adequately supported by scientific data. The following issues are raised: (1) industry-funded research studies which result in negative findings sometimes do not get published; (2) placebo washout procedures may bias results in some studies; (3) there are serious questions about the integrity of the double-blind procedure; (4) the 'true' antidepressant drug effect in adults appears to be relatively small; (5) there is minimal evidence of antidepressant efficacy in children; (6) side effects are fairly common even with the newer antidepressants; (7) combining medications raises the risk for more serious complications; (8) all antidepressants can cause withdrawal symptoms; (9) genetic influences on unipolar depression appear to be weaker than environmental influences; (10) biochemical theories of depression are as yet unproven; (11) biological markers specific for depression have been elusive; (12) dosage and plasma levels of antidepressants have been minimally related to treatment outcome; (13) preliminary evidence suggests that patients who improve with cognitive-behavioral psychotherapy show similar biological changes as those who respond to medication, and (14) the evidence suggests that psychological interventions are at least as effective as pharmacotherapy in treating depression, even if severe, especially when patient-rated measures are used and long-term follow-up is considered.     

Alternative approaches to refractory depression in bipolar illness

Thus, there appears to be a large variety of approaches to refractory bipolar depression. In contrast to several decades ago, wherein augmentation of lithium with antidepressants and neuroleptics was essentially the only treatment mode available, a panoply of treatment options now exist. However, their relative efficacy in different illness subtypes and stages remains to be better delineated, as do their optimal sequencing and use in combination in individual patients. It is the opinion of these authors and many of our colleagues in the field that initial use of several mood stabilizer drugs in combination may have a preferable long-term outcome in some rapid cycling patients, compared with the immediate use of a unimodal antidepressant with an inadequate single mood stabilizer, although this remains to be systematically studied. The use of thyroid augmentation strategies would appear to have merit in relationship to not only the potential treatment of lithium-related hypothyroidism, but also in augmenting antimanic and antidepressant effects. As one moves toward some of the complex combination treatment strategies discussed in this chapter, one has to be particularly careful about drug interactions and their potential for toxicity as well as therapeutic effects. Perhaps a prevailing guideline would be to use these agents more carefully in combination therapy than in monotherapy, with slow upward titration of dose to individual patients' side effects thresholds, even in preference to targeting of conventional blood level windows. In this way, side effects can be avoided during the assessment of complex combination regimens. In addition, one should be aware of potential pharmacokinetic interactions. For example, with the addition of valproate to carbamazenine, one should reduce the dose of carbamazepine, as valproate will not only increase the free fraction of carbamazepine based on displacement of protein binding, but will lead to increased accumulation of carbamazepine-10,11-epoxide. This epoxide is not measured in conventional assays but could contribute to the side effects profile (Ketter and Post, 1994). Similarly, valproate will markedly increase blood levels of lamotrigine; the starting dose of this agent should be substantially lower than conventional dosage when these two drugs are used in combination. We suggest the utility of detailed mapping with a formal system-such as the Life Chart Methodology (LCM) (Leverich and Post, 1996)-of mood fluctuation vs. medications in order to optimize and rationalize complex combination therapy. In this way, not only can the nuances of partial response be better defined, but also basic decisions about the therapeutic index and relative likelihood of response can be more readily assessed. We have discussed the other merits of the life chart method as an important clinical treatment tool as well as a research tool in other venues, but reemphasize its potential great importance in the treatment of refractory cyclic bipolar patients, in whom an initial period of remission of depression may, in many instances, be as likely attributable to the natural course of illness as the current intervention being offered. As such, it behooves the clinician to have a systematic database for the more subtle issues of dose titration and sequential addition of medications in complex combination regimens. In the face of inefficiency to one combination strategy, how one moves to the next strategy remains a highly individualized, clinically-based algorithm. We suggest the potential utility of moving towards a new set of mood stabilizers and then repeating some of the unimodal antidepressant additions and augmentation trials in an attempt to overcome refractory depression. Refractory depression in bipolar patients should be viewed as a medical emergency in light of the high potential for suicide in the illness in general (Chen and Dilsaver, 1996) and in patients who have either sustained or episodic refracto     

Treatment of refractory depression

Treatment of refractory depression is a common challenge for mental health professionals. To assure optimal treatment, the clinician should first determine that adequate dosage has been employed for an adequate duration. Next there are a variety of augmentation strategies or alternative antidepressants that could be considered. This report reviews the evidence supporting these strategies, describes their implementation, compares their effectiveness, and offers suggestions for approaching the array of treatments available.     

Cognitive therapy for depression: Conceptual issues and clinical efficacy.

Cognitive therapy has emerged as one of the most promising psychosocial interventions for the treatment of depression. It appears to be at least the equal of alternative interventions (including pharmacotherapy) with respect to acute treatment. In addition, there are indications that it may reduce risk of symptom return after treatment termination. Nonetheless, design limitations reduce the certainty with which such conclusions can be drawn. Furthermore, tests of its efficacy have largely been limited to nonbipolar outpatient (or subclinical) samples. At this time, cognitive therapy is best considered a promising, but as yet not adequately tested, intervention for the treatment of depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive-compulsive disorder responses

Considerable evidence is now available to support the pivotal role of the serotonin (5-HT) system is exerting the antidepressant response in humans. Different type of antidepressant treatments enhance 5-HT neurotransmission via different pre- or postsynaptic mechanisms. The time course for the occurrence of these adaptive changes in the brain of laboratory animals is consistent with the delayed onset of the antidepressant response in humans. The drugs effective in obsessive-compulsive disorder (OCD) also enhance 5-HT neurotransmission in brain regions involved in mediating OCD symptoms but with a more prolonged delay, consistently with the larger time necessary to obtain therapeutic effect in OCD than in depression. The elucidation of these mechanisms of action lead to the development of new pharmacologic strategies to potentiate the therapeutic effect of the drugs currently available and the identification of novel targets to accelerate and further improve treatment response in depression and OCD.     

Psychopharmacologic treatment of depression in the medically ill

Appropriate selection of an antidepressant agent in medically ill patients requires a careful risk-benefit assessment matching the pharmacokinetic and pharmacodynamic properties of the drug being considered against the patient's physiological vulnerabilities, potential for drug interactions, and primary symptoms of the patient's depression. While in the past antidepressant drug selection was limited by the almost sole availability of the tricyclic antidepressants, newer drugs such as selective serotonin reuptake inhibitors, bupropion, and venlafaxine have vastly simplified treating depression in the medically ill. In refractory cases of depression in patients with medical illness, electroconvulsive therapy can be used with appropriate anesthetic management.     

Fluoxetine

Fluoxetine was developed as an antidepressant drug. It is more effective than placebo, but a dose-effect relation has not been established. Fluoxetine is almost as effective as tricyclic antidepressant drugs, but the available studies do not allow accurate comparisons. Fluoxetine may be less effective than tricyclic antidepressant drugs for the treatment of inpatients with severe melancholic depression, and it should not be the first choice of a drug for them. Fluoxetine may be most appropriate for patients with moderate depression who can be treated as outpatients. If there is little improvement after treatment for four to six weeks, an alternative treatment should be offered. Fluoxetine does not have the anticholinergic, hypotensive, and sedative effects of tricyclic antidepressant drugs and has no particular cardiovascular effects; overdoses do not cause serious toxic effects. Nausea, anorexia, insomnia, and nervousness--the most common side effects--may be controlled with a careful adjustment to the dose. Clinically important drug interactions may occur with monoamine oxidase inhibitors, tricyclic antidepressant drugs, and other drugs. The published data on the antidepressant effect of fluoxetine do not fully explain its popularity. One may speculate that fluoxetine has psychobiologic effects not strictly related to the biology of depression and that it acts primarily as a mood- or affect-modulating agent.     

Treating major depression in primary care practice: an update of the Agency for Health Care Policy and Research Practice Guidelines

The Depression Guideline Panel of the Agency for Health Care Policy and Research in 1993 published recommendations for treating major depression in primary care practice that were often based on studies of tertiary care psychiatric patients. We reviewed reports of randomized controlled trials in primary care settings published between 1992 and 1998. This evidence indicates that both antidepressant pharmacotherapy and time-limited depression-targeted psychotherapies are efficacious when transferred from psychiatric to primary care settings. In most cases, the choice between these treatments should depend on patient preference. Studies to date suggest that improving treatment of depression in primary care requires properly organized treatment programs, regular patient follow-up, monitoring of treatment adherence, and a prominent role for the mental health specialist as educator, consultant, and clinician for the more severely ill. Future research should focus on how guidelines are best implemented in routine practice, since conventional dissemination strategies have little impact.     

Let''s clear the air of that nocturnal miasma. Cigar anyone?

A significant number of patients suffer psychological complications as a consequence of abortion, and 10-20% experience severe depression. The risk factors for such psychological complications originate with abortions performed under pressure, eugenic abortions, or late abortions, and with cultural or religious hostility against abortion. The response to abortion consists of four phases: phase 1 is short and comprises the immediate reaction and alleviation that the pregnancy is over; phase 2 can last for several weeks or months, with anxiety and even guilt being experienced by 20% of women 2 years after the abortion; phase 3 corresponds to a pathological phase, that is, when anxiety is transformed into disease in 10-20% of women (symptoms of this depressive disease include insomnia, crying, inability to concentrate, anxiety, and panic attacks); phase 4 consists of reactivated mourning. Treatment depends on the phase: for anxiety, counseling is indicated; for depression, anti-depression drugs; however, these are contraindicated in the first trimester if the patient becomes pregnant. For breast-feeding mothers, tricyclic antidepressants are indicated and during such treatment counseling should be suspended. Although the effects of such treatment methods have not been adequately assessed, it could be concluded that they do not cause any harm. The efficacy of treatment choices needs to be studied.     

Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge?

A growing body of literature describes the effects of estrogen and other gonadal steroids on the central nervous system. The ability of estrogen to modulate serotonergic function, in particular, raises the possibility that sex steroids may play a role in the mechanisms associated with depression and its treatment. This review will focus on those aspects of the estrogen-serotonin interaction that relate to possible increased vulnerability to affective disorders and on hormonal treatments that may be clinically applicable to women. After a discussion of the potential relationship between estrogen and mood disorders across the female life cycle, a model is proposed in which differential sensitivity to mood disorders explains the differential response by some women to periods of normal hormonal changes. Possible serotonin receptor-mediated and intracellular mechanisms by which estrogen may exert its effects on mood are also reviewed. These are compared to putative mechanisms of standard antidepressant effect. Lastly, treatment studies in which estrogen has been used as 1) monotherapy for depression, 2) an augmentation strategy, or 3) a prophylactic intervention against recurrence of depression are reviewed.     

Drug resistance in endogenous depression. Part I. Refractoriness to antidepressants in patients with depression admitted to a psychiatric clinic for the first time

The efficacy of antidepressive treatment (mainly pharmacotherapy) was evaluated among 284 patients, admitted for the first time to the hospital with the diagnosis of endogenous depression. The first antidepressant therapy was found effective in 58% of the patients. Furthermore treatment with other antidepressants in the patients not responding to the initial therapy was successful in 57% of the cases. Drug resistance (defined as no therapeutical effect after 2 adequate courses of antidepressant treatment) was established in 7% of this sample. It was established that the drug resistance is more frequent after the 45th year of life. No relation between the drug resistance and sex, type of affective disorder, life events or somatic disorders were found.     

Management of the depressive component of bipolar disorder

Acute bipolar depression (ABD) and breakthrough depression occurring during maintenance therapy of bipolar disorder are associated with significant morbidity and an increased risk of suicide. Lithium is an effective mood stabilizer for ABD, but its onset of antidepressant action is slow and additional antidepressant therapy is often prescribed. The extent to which other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant activity is unclear. Preliminary initial research suggests three potential advantages that selective serotonin reuptake inhibitors have over tricyclic antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a lower frequency of antidepressant-induced mania. Bupropion may also have significant advantages. However, further research is needed to confirm these findings. Monoamine oxidase inhibitors are the antidepressant of choice for atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest response rate of all treatments for ABD. Further research is needed to explore combination treatments with mood stabilizers and antidepressants for the effective treatment of ABD.     

Risk-benefit assessment of newer versus older monoamine oxidase (MAO) inhibitors

The first generation of monoamine oxidase (MAO) inhibitors fell into disuse because of poor efficacy in major depression with melancholia and/or endogenous depression, and because of poor tolerability (drug interactions and the 'cheese' effect). New MAO inhibitors, reversible inhibitors of MAO-A (RIMAs), are able to induce a reversible and specific inhibition of MAO-A. Consequently, the inhibition of MAO is quicker and the dose-response relationship improved, such that dosage adjustment is easier. Also, no carry-over effect once treatment is terminated is observed. The frequency and severity of drug interactions with RIMAs is reduced, although coadministration with pethidine (meperidine) or dextromethorphan should still be avoided. No specific subgroup of patients with depression has shown a better or worse response to RIMAs. The presence of melancholia in major depression, or the existence of endogenous depression, are not predictive of reduced efficacy compared with tricyclic antidepressant (TCA) reference compounds. Dysthymic patients have shown a good response to both RIMAs and TCAs independent of the co-existence of a major depressive episode. Older MAO inhibitors are more effective than TCAs in the treatment of atypical depression, and further studies are needed to confirm if this is true for RIMAs. Long term studies to evaluate the effects of RIMAs on disease recurrence are also required. RIMAs are better tolerated than older MAO inhibitors, including use in subgroups particularly at risk of adverse effects such as the elderly. Overall, RIMAs appear to represent therapeutic progress in the treatment of depression in terms of both efficacy and tolerability.     

Buspirone augmentation of antidepressant therapy

Thirty outpatients meeting DSM-III-R or DSM-IV criteria for major depression, single or recurrent episode, and failing to respond to an adequate trial of an antidepressant (>6 weeks at recommended dosage) received buspirone (20-30 mg/day) for 4 or 5 weeks in addition to their existing antidepressant. Of the 22 patients who had buspirone added to their selective serotonin reuptake inhibitor antidepressant regimen (fluoxetine, paroxetine, or citalopram), 59% (13/22) showed complete or partial remission of their depressive symptomatology. Similarly, 63% (5/8) of patients treated with buspirone in addition to clomipramine showed complete or partial remission. The mean score on the Clinical Global Impressions Scale fell by 64% (from 4.7 to 1.7; p < 0.0001) in treatment responders (complete and partial). No serious side effects were observed during combination therapy. Seventy-nine percent (11/14) of initial responders (both complete and partial) who remained on augmentation therapy for at least 4 months were symptom-free at follow-up. Buspirone augmentation may produce marked clinical improvement in depressed patients who are initially unresponsive to standard antidepressant therapy.     

Mortality in depressed patients treated with electroconvulsive therapy and antidepressants

The treatments of 519 depressed patients hospitalized from 1959 to 1969 were compared in a three-year follow-up study with particular reference to mortality. The electroconvulsive therapy (ECT) group had a significantly lower mortality than the inadequate antidepressant treatment group (P less than .05) and the group that received neither ECT nor antidepressants (P less than .025). Although the adequate antidepressant treatment group had a low mortality, statistically significant differences between this and other treatment groups could not be documented. Nonsuicidal deaths (P less than .005), and particularly myocardial infarctions (P less than .01), were significantly more frequent in the inadequately treated group compared to the adequately treated group. The superiority of adequate treatment is especially striking among men and among the older age groups. The results underscore the importance of adequate treatment of depression, especially in the older man.