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.     

Lithium and desipramine versus desipramine alone in the treatment of severe major depression: a preliminary study

Improvement following lithium augmentation is well-documented in depressed patients resistant to tricyclic antidepressants. However, response latency to lithium augmentation is extremely variable, suggesting other mechanisms may be involved. To evaluate whether long-term tricyclic treatment is necessary for lithium augmentation's effect, the rapidity and magnitude of response to lithium combined with desipramine from the start of treatment was compared to desipramine alone in severely depressed patients. Patients with DSM-III-R major depression were randomized to double-blind, placebo-controlled treatment with either lithium + desipramine or placebo + desipramine for 4 weeks. Response criteria were based on Hamilton Depression Rating Scale scores and global improvement. Analysis of covariance of Hamilton scores demonstrated that lithium + desipramine was superior to placebo + desipramine at week 1 (P < 0.009), week 2 (P < 0.028), and week 3 (P < 0.07), although not at week 4. There were more responders to the combination than to monotherapy (P < 0.042). These preliminary data suggest that lithium + desipramine may have some efficacy in severely depressed patients. Further studies with larger samples are needed to confirm these findings.     

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.     

The severity of major depression and choice of treatment in primary care practice.

The Agency for Health Care Policy and Research Depression Guideline Panel recommended pharmacotherapy as the 1st-line treatment for more severely depressed primary care patients, but research supporting its recommendation has not been conducted with this population. A post hoc analysis was conducted, therefore, with data gathered in a randomized controlled trial about the relationship between initial level of depressive severity and functional ability, treatment with nortriptyline hydrochloride (NT) or interpersonal psychotherapy (IPT), and clinical course over 8 months among primary care patients experiencing major depression. Treatment type was unrelated to clinical course among more severely depressed patients (baseline 17-item Hamilton Rating Scale for Depression [HRSD] score ≥20). However, less severely depressed patients (baseline 17-item HRSD score ≤19) who were prescribed NT improved significantly more rapidly during the initial 3 months of treatment than patients provided with IPT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Weight gain in depression remitted with antidepressants: pharmacological or recovery effect?

BACKGROUND: Depression remission is often associated with weight gain. It is not clear if weight gain is caused by a pharmacological effect of antidepressants, or if instead it is an effect of recovery from depression. The aim of this study was to try to clarify this point. METHODS: One hundred consecutive unipolar/bipolar remitted depressed private practice outpatients (DSM-IV diagnoses with structured interview) were interviewed with structured questions about weight changes occurring during depression and remission. Comparisons were made between remitted weight gainers and remitted nonweight gainers. RESULTS: Seventy-two percent of patients showed weight gain when they remitted from depression, in comparison with their weight when they were depressed. No significant differences were found in age, gender, diagnoses, duration of remission, use of tricyclics, tricyclic-SSRI combination, benzodiazepines, neuroleptics, and mood stabilizers in remitted weight gainers versus nonweight gainers. SSRIs were significantly more used in remitted nonweight gainers. Significantly more weight loss and less weight gain when depressed were found in remitted weight gainers versus nonweight gainers. CONCLUSIONS: These findings suggest that weight gain in remitted depressed patients may not necessarily be a pharmacological effect of antidepressants, but may rather be an effect, at least in part, of recovery from depression.     

Auditory event related potentials in major depression: prolonged P300 latency and increased P200 amplitude

BACKGROUND: Some studies have shown disturbances in auditory event related potentials (AERPs) in patients with major depression. METHODS: In this exploratory study, the late AERP components, N100 (latency), P200 (amplitude and latency) and P300 (amplitude and latency) were recorded in 68 subjects, i.e. 39 major depressed subjects, with (n=4) or without (n=35) cognitive deterioration, 18 patients with Alzheimer's dementia (SDAT) and 11 normal volunteers. Twenty-five major depressed patients had repeated measurements of AERPs both before and after treatment with antidepressants. RESULTS: Major depressed subjects without cognitive deterioration had significantly higher P300 latency and P200 amplitude than normal volunteers. SDAT patients and major depressed patients with cognitive impairment had a significantly higher P300 latency than depressed patients without cognitive impairment. In the latter, no significant alterations in any of the AERP components upon subchronic treatment with antidepressants were recorded. Nonresponders to antidepressant therapy had significantly higher pretreatment P300 latency and P200 amplitude than responders to treatment (P=0.006) and normal volunteers (P=0.0004). CONCLUSIONS: The findings may suggest that delayed P300 latency as well as increased P200 amplitude accompany major depression and may predict a nonresponse to subsequent antidepressive therapy.     

The efficacy, safety and tolerability of antidepressants in late life depression: a meta-analysis

BACKGROUND: To determine the efficacy, safety and tolerability of antidepressants in depressed elderly patients. METHODS: Search for randomized controlled double-blind studies evaluating atypical antidepressants (ATYPs), reversible inhibitors of monoamine oxidase-A, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants in moderate/severe depressed patients > or = 60 years for > or = four weeks. The random effects model (single-arm; comparative) was used to aggregate efficacy, safety and dropout. RESULTS: No difference in single-arm aggregation of outcomes for four antidepressant classes. Comparative analyses showed no statistical difference between outcomes, except SSRIs had a higher response rate than ATYPs. CONCLUSION: Elderly show no differences in antidepressant class outcomes. LIMITATIONS: Heterogeneity and lack of power. CLINICAL RELEVANCE: There is little advantage for antidepressant classes over another in the aged.     

Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.     

Treatment of depression in bipolar disorder: new directions for research

The objective of the study was to review the clinical literature on the acute, somatic treatment of the depressed phase of bipolar disorder. We reviewed all available published studies of "standard" somatic treatments (lithium, antidepressant and anticonvulsant agents, and electroconvulsive therapy [ECT]) reporting three or more depressed bipolar patients who were not psychotic, rapid cycling, or previously treatment refractory. We also reviewed all studies of "nonstandard" pharmacologic treatments involving even a single case of a depressed bipolar patient. Data sources included the MEDLINE database and relevant references from articles obtained in this search and in major reviews. Five of seven studies comparing ECT with antidepressant agents find ECT more efficacious. Eight of nine controlled comparisons find lithium superior to placebo in depressed bipolar patients. Three controlled comparisons of lithium to tricyclic antidepressants suggest that lithium is equivalent to tricyclic drugs in such patients. Three double-blind, controlled studies indicate that carbamazepine is more effective than placebo. Limited data on other antidepressant classes suggest that monoamine oxidase inhibitors, bupropion, and serotonergic agents may offer some advantages over tricyclic antidepressants in this population. Some "nonstandard" treatments also show some potential in bipolar patients. The possibility of switching into a manic episode is an important consideration with many of the agents studied, although little remains known about spontaneous versus treatment-associated mood shifts. In contrast to the extensive literature on the acute treatment of the manic phase of bipolar disorder and on the prophylaxis of manic and depressive episodes, there are few studies of treatment of the depressed phase of bipolar disorder, and their results generally are limited or inconclusive. Lithium generated a revolution in psychiatric treatment, but the treatment of the depressed phase of bipolar disorder remains a relatively neglected corner of the field. Several study designs may help to augment knowledge in the treatment of bipolar depression.     

Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms

The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4B, and PDE4D) was examined. The treatments tested included representatives of four major classes of antidepressants: selective reuptake inhibitors of serotonin (sertraline and fluoxetine) or norepinephrine (desipramine), a monoamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Expression of PDE4A and PDE4B, but not PDE4D, mRNA and immunoreactivity were significantly increased in rat frontal cortex by chronic administration of each of the four classes of antidepressants. We also found that antidepressant administration significantly increased the expression of PDE4B mRNA in the nucleus accumbens, a brain region thought to mediate pleasure and reward that could also contribute to the anhedonia often observed in depressed patients. In contrast, expression of PDE4A and PDE4B were not influenced by short-term treatment (1 or 7 d) and were not influenced by chronic administration of nonantidepressant psychotropic drugs (cocaine or haloperidol), demonstrating the time dependence and pharmacological specificity of these effects. Upregulation of PDE4A and PDE4B may represent a compensatory response to antidepressant treatment and activation of the cAMP system. The possibility that targeted inhibition of these PDE4 subtypes may produce an antidepressant effect is discussed.     

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.     

Immunodetection and quantitation of imidazoline receptor proteins in platelets of patients with major depression and in brains of suicide victims

BACKGROUND: Imidazoline receptors are a newly discovered family of receptors, some of which, like alpha 2-adrenoceptors, have a presynaptic inhibitory effect on the release of norepinephrine. The aim of this study was to identify by immunodetection imidazoline receptor proteins in human platelets and the brain to assess their status in depression and suicide. METHODS: Platelets were collected from 26 drug-free depressed patients and 26 controls. Specimens of frontal cortex (Brodmann area 9) were collected from 13 suicide victims and 11 controls. Levels of imidazoline receptor proteins were assessed by immunoblotting techniques. Solubilized imidazoline receptors were separated by gel electrophoresis, transferred to nitrocellulose membranes, labeled with a specific anti-imidazoline receptor antiserum, and quantitated by image analysis. RESULTS: Platelet and brain membranes expressed similar 45-kd imidazoline receptor proteins, and their mean +/- SEM immunoreactivities were found to be increased in depressed patients (platelets, 40% +/- 5%) and suicide victims (brain, 51% +/- 14%). Platelets also expressed a 35-kd imidazoline receptor protein that was also found to be up-regulated in depressed patients (21% +/- 4%). In contrast, brain membranes did not express this 35-kd protein but revealed a 29/30-kd imidazoline receptor protein that was found to be down-regulated in suicide victims (19% +/- 3%). In a subset of depressed patients who underwent antidepressant treatment, a change in the immunoreactivity of the up-regulated 45-kd platelet imidazoline receptor protein (-35% +/- 5%), but not of the 35-kd protein, was observed. CONCLUSION: The results support a role for the newly discovered imidazoline receptors (mainly the 45-kd receptor expressed in the brain and platelets) in the pathogenesis of depression.     

Effects of intravenous milrinone followed by titration of high-dose oral vasodilator therapy on clinical outcome and rehospitalization rates in patients with severe heart failure

This study evaluated the efficacy of intravenous milrinone in improving hemodynamics and facilitating the titration of high-dose oral vasodilator therapy to improve clinical status. Fourteen patients (mean age 52 +/- 12 years) with severe heart failure and a left ventricular ejection fraction of 18 +/- 6% underwent right-side heart catheterization and an intravenous milrinone infusion followed by titration of oral vasodilator and diuretic therapy. Milrinone significantly (p <0.05) improved right atrial pressure (12 +/- 5 to 8 +/- 5 mm Hg), pulmonary capillary wedge pressure (23 +/- 7 to 15 +/- 7 mm Hg), cardiac index (1.9 +/- 0.4 to 3.4 +/- 0.5 L/min/m2), systemic vascular resistance (1,809 +/- 526 to 891 +/- 144 dynes/s/cm(-5)), and pulmonary vascular resistance (285 +/- 151 to 163 +/- 68 dynes/s/cm(-5)), which was maintained in 10 patients with titration of high-dose oral vasodilator therapy. Oral angiotensin-converting enzyme inhibitor and diuretic doses were increased 318% and 89%, respectively. Four patients also received hydralazine to optimize hemodynamics. New York Heart Association functional class improved from 3.8 +/- 0.4 to 2.6 +/- 0.6 following therapy. Ten patients who responded to therapy had fewer hospitalized days during the subsequent year compared with the year before treatment (4 +/- 17 vs 17 +/- 15), and no patient died. In contrast, the 3 patients who responded poorly to therapy tended to have more hospitalized days at 12 months compared with pretreatment (31 +/- 11 vs 20 +/- 18; NS); 1 patient died. We conclude that intravenous milrinone followed by optimization of oral medical therapy may be used as a therapeutic trial to identify patients in need of cardiac transplantation.     

Treatment response of depressed outpatients unresponsive to both a tricyclic and a monoamine oxidase inhibitor antidepressant

BACKGROUND: Data regarding effective treatment options for the minority of patients refractory to initial antidepressant trials are essential to guide therapeutic choices and to sustain the hope of patients and perseverance of clinicians. Few such data are available concerning the treatment of patients refractory to treatment with both a tricyclic antidepressant and a monoamine oxidase inhibitor given singly. METHOD: In a study of mood reactive depressed patients, most of whom met Columbia criteria for atypical depression, 20 patients refractory to vigorous 6-week double-blind trials of both imipramine and phenelzine given singly were given clinician's choice open treatment. A chart review of course in open treatment was conducted. RESULTS: Eleven patients (55%) had a full response to subsequent treatments, principally continued phenelzine and the combination of phenelzine with amitriptyline. Another 6 (30%) had at least moderate benefit from a variety of other treatments. CONCLUSION: These data suggest that even among patients who have failed to respond to two vigorous trials of different antidepressants, at least half appear to benefit from other pharmacologic regimens.     

Pharmacologic treatments effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical implications

OBJECTIVE: To review the efficacy of anxiolytics (alprazolam and azapirones) in major depressive disorder (MDD) and that of antidepressants in generalized anxiety disorder (GAD), thereby exploring the possible theoretical and clinical implications of this efficacy. METHOD: A Medline literature search was performed for the period January 1980 to September 1997 of randomized, double-blind comparison studies between anxiolytics and antidepressants in the acute treatment of adult patients with either MDD or GAD. RESULTS: Alprazolam, at doses double those generally recommended for anxiety disorders, appears to be as effective as tricyclic antidepressants (TCAs) in the acute treatment of mild to moderate MDD. Alprazolam was also found to have a more rapid onset of action than to TCAs, particularly for the improvement of anxiety, somatization, and insomnia. Two azapirones (buspirone and gepirone) also have demonstrated a modest acute antidepressant effect in preliminary studies, albeit only in a depressed outpatient sample with considerable anxiety at baseline. Finally, various antidepressant drugs (imipramine, trazodone, paroxetine) were shown to have, at the least, comparable efficacy to benzodiazepines (BZDs) in the acute treatment of GAD. CONCLUSIONS: The nonspecificity of treatment response suggests that GAD and MDD are 1) different expressions of a similar disorder with a common neurobiological substrate, 2) discrete diagnostic entities that respond to independent pharmacological effects of the same drugs, or 3) a combination of the two (heterogeneity hypothesis). The most relevant clinical finding is the efficacy of antidepressants in the acute treatment of GAD.     

Low-dose versus high-dose oxytocin augmentation of labor--a randomized trial

OBJECTIVE: Our purpose was to compare the efficacy and safety of low-dose versus high-dose oxytocin regimens in the augmentation of labor. STUDY DESIGN: Three hundred ten term pregnancies requiring augmentation of labor underwent randomization to receive either a low-dose or high-dose oxytocin augmentation regimen. Maternal demographics, labor-delivery data, and neonatal outcome were compared. RESULTS: The high-dose oxytocin group had a significantly lower cesarean section rate, regardless of parity (10.4% vs 25.7%, p < 0.001), with no differences in maternal complications and neonatal outcomes. The time needed to correct the labor abnormality was also significantly decreased (1.24 +/- 1.4 hours vs 3.12 +/- 1.6 hours, p < 0.001) in the high-dose group. CONCLUSIONS: The use of high-dose oxytocin regimen benefits both nulliparous and multiparous women requiring labor augmentation by significantly lowering both the time necessary to correct the labor abnormality and the need for cesarean section.     

Increased diurnal plasma concentrations of dehydroepiandrosterone in depressed patients

Activation of the hypothalamus-pituitary-adrenocortical system is a biological core symptom of depression. Although the regulation of cortisol secretion is well studied in this condition, there is no information about the diurnal activity of dehydroepiandrosterone (DHEA) secretion. Therefore, we studied 24-h DHEA plasma concentrations (every 30 min) in severely depressed patients (n = 26) and healthy controls (n = 33). We found depression to significantly increase diurnal minimal and mean DHEA plasma concentrations, whereas there was no effect on the diurnal maximal plasma concentration and the diurnal amplitude of DHEA. In particular, we found a parallel increase in mean DHEA (5.8 +/- 3.6 vs. 3.4 +/- 1.9 nmol/L; P < 0.003), cortisol (286 +/- 65 vs. 184 +/- 29 nmol/L; P < 0.0001) and ACTH (7.14 +/- 2.06 vs. 5.72 +/- 1.36 pmol/L; P < 0.002) plasma concentrations. The novel finding of parallel increases in diurnal DHEA and cortisol plasma concentrations in depressed patients has important implications for the regulation of the hypothalamus-pituitary-adrenocortical system in conditions of chronic stress and for the rationale of DHEA treatment in depressed patients.     

Comments and corrections on the contaminated rebar incident in Taiwan

OBJECTIVE: Alternate ways of administering antidepressants when oral intake is impossible are discussed. METHOD: Reviews of 1) the medical circumstances that preclude oral medication administration and 2) novel administration strategies for antidepressants were conducted. RESULTS: Consultation psychiatrists not infrequently encounter depressed patients who lack a functioning gastrointestinal tract and who thus cannot absorb oral antidepressant medication. Under these circumstances, antidepressants can be administered intravenously, by rectal suppository, or topically. CONCLUSION: There are options for administration of antidepressant medication when oral intake is impossible.     

Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties

The aim of this study was to assess the effect of a long-term course of high-dose i.v. pulses of calcitriol (CLT) on hyperparathyroid bone disease (HBD) and functional mass of parathyroid glands of chronically hemodialyzed uremic (CHU) patients. We prospectively studied nine CHU patients treated with CLT, 30 ng/kg/body wt, i.v., thrice weekly over a period of eight months. Plasma concentrations of intact parathyroid hormone (iPTH), bone GLA protein (bGLA) and bone isoenzyme of alkaline phosphatase (biALP) were sampled throughout. Transiliac bone biopsies were made before and after the start of CLT therapy. Double scanning scintigraphy of the neck with 201Tl-99Tc was made before, during and eight months after the start of the treatment. All patients but one, who later responded to higher than planned CLT doses, had significant decreases of plasma iPTH (F = 76; P < 0.0001; ANOVA). The mean pretreatment value of PTH was 966 +/- 160 (mean +/- SE) pg/ml and it had decreased significantly by the first week (T = 2.4, P < 0.04), and had fallen an average of 80% by the 35th week. Ionized plasma calcium concentration was 1.19 +/- .01 mmol/liter which rose significantly (F = 13.5; P < 0.0001) by the 14th week to maximal peak levels, averaging 1.34 +/- .02 mmol/liter. Changes in biALP were parallel to those of iPTH, while bGLA tended to increase immediately after the start of the therapy and to significantly decrease thereafter (T = 3.2; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Rates of flu-like infection in patients with affective illness

Studies of immunologic profiles of depressed patients are suggestive of chronic viral infection and several investigators have found specific viral protein in some depressed patients. Moreover, several psychotropic drugs have anti-viral activity and can inhibit viral replication. In this preliminary report, we retrospectively examined the rate of reported flu-like episodes before and during psychotropic drug treatment in 236 affectively ill patients: 177 receiving lithium prophylaxis and 59 receiving chronic antidepressant medication. We observed a small but significant reduction in the mean rate of reported flu-like illness during lithium therapy (P < 0.001), with a greater reduction in men vs. women (P < 0.05). We also found a modest reduction in reported flu-like illness during chronic treatment with antidepressants (P = 0.08). Although these observations are preliminary in nature, they complement earlier reports that some psychotropic drugs may have anti-viral activity.