Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation

Clinicians who treat major depression are faced with a bewildering choice of antidepressants. Given that all have a lag period before they are effective, choice of the right antidepressant can potentially minimize the duration of symptoms, reduce cost and enhance compliance. Unfortunately, there is very little evidence upon which to base such a decision. We developed a treatment algorithm for non-psychotic, unipolar major depression, and applied it in our clinic. It includes progression from a specific serotonin reuptake inhibitor (SSRI), usually fluoxetine, from a dose of 20 mg to a dose of 40 mg in patients who do not respond. Non-responders to this dose receive augmentation with triiodothyronine (T3, 25-50 microg). All interventions are for fixed time periods and guided by overall clinical improvement as defined by the Clinical Global Inventory. Ninety patients commenced open-label treatment with 20 mg SSRI (fluoxetine, n=81; paroxetine, n=9). Seventy-four patients completed 4 wk of treatment and 44 (48.9%) were responders (intent to treat analysis). Raising the SSRI dose to 40 mg for a further 2 wk was effective in only 5 patients (16.6%). Non-responders to SSRI were significantly more depressed at baseline as reflected by their rating scales scores. Addition of T3 was effective in 10 out of 16 women (62.5%) while none of the 9 males responded. Although values were within the normal range, patients who responded to T3 had higher serum thyroid-stimulating hormone levels than those who did not. Our experience with algorithm-based treatment of unipolar, non-psychotic major depression in outpatients suggests that more than 40% of patients will not respond to initial treatment with an SSRI even when the dose is increased to 40 mg/d; that severity of depression may be an important predictor of response and that T3 may be useful as an augmenter of response in SSRI non-responders but may be less effective in men than in women. The effect of T3 may be related to thyroid function even within the normal range.     

Treatment of resistant depression. Review on the efficacy of various biological treatments, specifically in major depression resistant to cyclic antidepressants

The biological treatment of depression includes administration of psychoactive drugs (cyclic antidepressants, MAO-inhibitors, neuroleptics and lithium), use of certain substances which in small amounts are normally present in food such as, L-tryptophan (L-TP) and L-5-hydroxytryptophan (L-5HTP), electroconvulsive therapy (ECT) and various manipulations of the sleep-wake rhythms. This paper reviews the literature on the efficacy of these treatments in patients resistant to earlier adequate treatment(s) with cyclic antidepressants. Subsequently the following strategy for the biological treatment of (non-psychotic) major depression is suggested: (1) administration of a cyclic antidepressant; (2) if after a period of 4 to 6 weeks a patient has not responded to an adequate dose, another cyclic antidepressant should be tried, adding lithium if the patient still does not respond; (3) MAO-inhibitors and (4) ECT. In psychotic depression the suggestions for the first, third and fourth steps are the same. In the second step, the cyclic antidepressant should be combined with a neuroleptic.     

Initial lithium augmentation improves the antidepressant effects of standard TCA treatment in non-resistant depressed patients

The hypothesis was tested that an initial lithium-tricyclic antidepressant (TCA) combination has a better antidepressant effect than standard TCA treatment in non-refractory depression at the beginning of an episode. Twenty bipolar melancholic type depressed inpatients under lithium-TCA treatment were compared with 20 patients with the same diagnosis and TCA-placebo treatment for 5 weeks under double-blind conditions. All patients were male. Initial lithium-TCA treatment reduced depressive symptoms significantly more than antidepressant treatment with TCA and placebo after 5 weeks, but not in weeks 1 or 2. It can be concluded that lithium augmentation of TCA treatment should be started even at the beginning of antidepressant TCA treatment to provide a better treatment response in those patients who will profit from long-term lithium prophylaxis, e.g. bipolar patients with melancholic type depression.     

Efficacy and mechanisms of action of lithium augmentation in refractory major depression

Lithium augmentation refers to the addition of lithium to an antidepressant in the acute treatment phase of patients with depressive episodes who have failed to respond satisfactorily to treatment with antidepressant monotherapy. This article reviews the clinical evidence and hypotheses on the mode of action of lithium augmentation. For this purpose, studies were identified by searching Medline and by scanning the references of published reviews and standard textbooks. With regard to efficacy, 28 prospective studies (with a total of 838 depressed patients) were identified. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation. A recent meta-analysis including only double-blind, placebo-controlled trials (N = 9) provided firm evidence that lithium augmentation has a statistically significant effect on response rate compared to placebo, and showed that lithium augmentation should be administered for at least 2 weeks to allow assessment of the patient's response. A recent double-blind, placebo-controlled trial revealed that responders to lithium augmentation should be maintained on the lithium-antidepressant combination for a minimum of 12 months. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly through a synergistic action of lithium and the antidepressant on brain 5-HT pathways. Neuroendocrine studies in humans on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined dexamethasone/CRH test. These results are in contrast to the established decline of HPA system activity during treatment with antidepressants. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment.     

Adjunctive lithium carbonate in nortriptyline-resistant elderly depressed patients

Recent reports supporting the use of lithium carbonate as an adjunct to tricyclic antidepressants for the treatment of refractory depression have not utilized standardized tricyclic antidepressant therapy, nor have they addressed the efficacy of lithium augmentation in a geriatric population. A 3-week open trial was added to the medication regimen of 15 elderly depressed inpatients who had already failed 4 weeks of therapeutic levels of nortriptyline. Treatment response was determined by the 17-item Hamilton Rating Scale for Depression (HAM-D). Two of 15 partial responders before lithium augmentation became complete responders. Of the remaining 13 "nonresponders" before lithium augmentation, one had a complete response, 7 had a partial response and 5 remained nonresponders. Although there was a mean HAM-D change of 8.3 points after lithium augmentation (24.7 +/- 5.9 to 16.4 +/- 6.8, p less than .001), when considering the previously reported similar efficiency of extended nonaugmented nortriptyline, these data do not strongly support lithium augmentation in elderly subjects who fail to respond after 4 weeks of nortriptyline. Further study is needed to determine what role, if any, lithium augmentation should play in the treatment of geriatric depression.     

A comparison of two antidepressant drugs

Summary A comparative trial of two antidepressant drugs on 100 out-patients extending over six weeks is described. Overall response to the drugs was not significantly different, and the overall favourable responses may be related to the inclusion of only mild and moderate cases. The occurence of some age and sex differences in response to treatment while probably spurious suggest a hypothesis that women over 40 with depression will respond better to imipramine while men under 40 with depression will show greater improvement on phenelzine. Both drugs appear to have clinical value in the treatment of an assortive group of mild and moderately depressed out-patients.     

Noradrenergic dysfunction and antidepressant treatment response.

The purpose of this study was to investigate differences in outcome following treatment with two different antidepressants in depressed patients according to their pretreatment hormonal response to clonidine. In all, 62 drug-free DSM-IV recurrent major depressed patients and 20 normal controls were studied. Patients were subsequently treated for 4 weeks with fluoxetine (n=28), or amitriptyline (n=34), and were then classified as responders or nonresponders according to their final Hamilton depression scale score. Compared to controls, depressed patients showed lower GH response to CLO (DeltaGH) (P<0.0002). One control (5%) and 35 depressed patients (56%) had blunted DeltaGH values. The efficacy of the two antidepressants was not significantly different: 15 patients responded to AMI (44%), seven patients responded to FLUOX (25%) (P>0.15). However, in the subgroup of patients with blunted DeltaGH levels, the rate of responders was higher for AMI (11/21) compared to FLUOX (1/14) treated patients (P<0.01). These results suggest that in depressed patients a blunted GH response to CLO could predict antidepressant response.     

Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients.

A study was carried out in which 135 mildly or moderately depressed outpatients were randomly allocated to one of five groups receiving six weeks' treatment weith antidepressant drugs. The groups received a tricyclic antidepressant (trimipramine; mean dose 106 mg at night) or a monoamine oxidase inhibitor (MAOI) (phenelzine or isocarboxazid; mean doses 45 and 32 mg/day respectively), or a combination of the two (phenelzine plus trimipramine or isocarboxazid plus trimipramine). Various scales were used to measure depression before and at one, three, and six weeks of treatment, and results were assessed blindly. The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments. Some differential indicators of response to the various antidepressants were found--for example, patients with initial complaints of dizziness, suicidal ideas, irritability, and insomnia and a longer duration of illness were more likely to respond to trimipramine--but these were of only modest significance. Side effects were not troublesome in any group. It is concluded that neither MAOIs nor MAOIs combined with tricyclic antidepressants are the treatment of first choice in unselected outpatients with mild or moderate depression.     

Drug treatment of depression in HIV-positive patients : safety considerations.

Safe and effective treatment of major depression, one of the most common comorbid conditions in individuals infected with HIV, significantly lowers morbidity and mortality from HIV disease. However, optimal treatment of both conditions is complicated by interactions between the disease processes as well as the pharmacological agents used to treat them. In patients with HIV it may be difficult to distinguish major depression from other physiological and emotional states that present with similar symptoms. Accurate diagnosis of major depression is thus complex and essential to preventing inappropriate exposure of patients to potentially harmful psychotropic medications. This review outlines important initial steps in making this diagnosis. All patients with HIV should be screened for depression by their medical providers and referred to a psychiatrist for full evaluation when necessary. The mainstay of treatment for major depression in patients with HIV disease is pharmacotherapy. Depressed patients with HIV respond to the same wide variety of antidepressant-class medications as depressed patients without HIV, including tricyclic antidepressants, paroxetine, fluoxetine and trazodone. Notably, new studies have also shown that some psychiatric medications can inhibit HIV replication. No particular antidepressant medication is superior for the treatment of depressed HIV-infected patients; however, the most important component of treatment of major depression in HIV-disease is patient adherence, which is highly influenced by antidepressant adverse effects. This review outlines adverse effects of antidepressant-class medications that are of particular concern in HIV-infected patients and describes pharmacological strategies for overcoming these potential barriers to medication adherence. This review also describes situations in which some adverse effects of antidepressant-class medications may be safely exploited to benefit depressed patients with HIV disease. Potential interactions between antidepressant-class medications and HIV medications, as well as pharmacological treatment strategies for treating the psychiatric adverse effects of HIV medications, are also discussed.     

The efficacy and tolerability of bupropion in the treatment of major depressive disorder

Major depressive disorder (MDD) is a highly recurrent condition associated with a substantial burden of disease. Antidepressants alone or in combination with psychotherapy are the mainstay of treatment. Evidence demonstrates that antidepressant agents are significantly more efficacious than placebo in treating MDD, and antidepressants of different types have similar efficacies. However, not all patients respond to initial pharmacological treatment, suggesting the need for antidepressants with different mechanisms of action. Bupropion is a second-generation antidepressant, with a mechanism of action different from most antidepressants, in that it is a dopamine and norepinephrine reuptake inhibitor. Bupropion has demonstrated efficacy in the treatment of MDD, measured by Hamilton depression rating scale total and clinical global impressions severity and improvement scores, the proportion of responders, the proportion of patients in remission of disease, the prevention of relapse and beneficial effect on a range of health-related quality of life measures. With an efficacy that is at least similar to most other common antidepressants, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other second-generation drugs, bupropion has a favourable acceptability and tolerability profile. In particular, it has a minimal effect on sexual function, comparable or lower rates of somnolence than placebo, and is associated with lower rates of weight gain and sedation than some other commonly used antidepressants. Combination therapy of bupropion with other second-generation antidepressants has been shown to improve outcomes in patients failing antidepressant monotherapy. Bupropion is approved for the treatment of MDD in the USA, Canada and many countries in Europe, and current evidence-based guidelines reinforce its place as an efficacious and well-tolerated treatment option in the pharmacological management of MDD.     

The use of dexamethasone in elderly patients with antidepressant-resistant depressive illness.

Many depressed patients do not respond to first-line antidepressant treatment. Dexamethasone is a synthetic steroid which may have antidepressant properties. Its use in two elderly patients with resistant depression is reported. Both patients appeared to benefit from the treatment. The possible modes of action of this treatment, and its potential benefits to the elderly, are discussed.     

The astroglial protein S100B and visually evoked event-related potentials before and after antidepressant treatment

Rationale S100B is an astrocytic, calcium-binding protein which in nanomolar concentrations has neuroprotective and regenerating effects on neurons and glial cells. Increased levels have been shown to be positively correlated with therapeutic response in major depression. Event-related potentials (ERP) have been reported to be impaired in depressed patients.Objectives The aim of our study was to assess the relationship between S100B and visually evoked ERP in depression.Methods ERP and S100B serum concentration were studied in 18 patients with major depression, before and after 4 weeks of antidepressant treatment.Results The S100B concentration in patients was increased at intake and after 4 weeks of treatment compared to healthy controls. Initially increased P3-latency normalized and P2-latency significantly decreased after 4 weeks of treatment, although only in patients with clearly elevated initial S100B levels (mean plus 2 SD of the healthy controls).Conclusion The neuroregenerative activity of moderately increased S100B levels in major depression might be a factor contributing to a decrease of prolonged ERP parameters in major depression during antidepressant treatment.     

The dexamethasone suppression test as a predictor of antidepressant response

There is some evidence to suggest that dexamethasone suppression test (DST) results obtained prior to treatment for depression might aid in selecting the proper type of antidepressant medication. Forty endogenously depressed outpatients were evaluated with the DST and 12 (30%) were identified as nonsuppressors. All patients were then treated with desipramine (150–350 mg/day). Plasma concentrations of desipramine were monitored to assure that therapeutic levels were achieved. At 5 weeks of treatment, patients were characterized as treatment responders or nonresponders on the basis of change in Hamilton Depression Scale scores.     

Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission. The overall therapeutic efficacy of lofepramine is comparable to that of imipramine, amitriptyline, clomipramine, maprotiline and mianserin in patients with depression of varying severity, and coexisting anxiety. Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose. Thus, providing its apparent favourable side effect profile is confirmed in practice, lofepramine may be a valuable alternative for treatment of the depressed patient where a tricyclic is indicated.     

Clinical efficacy of agomelatine in depression: the evidence

Despite the advances of recent decades, there is still an urgent need for antidepressants with improved efficacy, safety and tolerability. Agomelatine is a new antidepressant with an innovative pharmacological profile. It is the first melatonergic antidepressant, and is a potent agonist of melatonin receptors (MT1 and MT2) with 5-HT2C antagonist properties. The efficacy of 25 mg/day agomelatine in treating major depressive disorder (MDD) has been demonstrated in a number of placebo-controlled studies. Evidence of improvement in depressive symptoms was observed in a dose-ranging study in which 25 mg/day agomelatine was significantly better than placebo, whatever the rating scale used (Hamilton Rating Scale for Depression, Clinical Global Impression, and Montgomery-Asberg Depression Rating Scale). These results have been confirmed in two similarly designed placebo-controlled studies. Agomelatine also produces a significant improvement in anxiety compared to placebo, according to Hamilton Rating Scale for Anxiety scores. The efficacy of agomelatine has been studied in subpopulations with more severe depression, demonstrating its efficacy in these difficult-to-treat patients. In view of the available data on agomelatine, this antidepressant can be regarded as an innovative treatment for MDD patients, offering a new approach in the management of depressed patients.     

What next? A review of pharmacologic strategies for treatment resistant depression

When an antidepressant fails to help a depressed patient, clinicians are faced with the daunting task of choosing the next treatment. Several pharmacologic and nonpharmacologic strategies exist, but the evidence available to help clinicians decide which treatment will be most effective is limited. To help clinicians evaluate the literature on treatment resistant depression (TRD), we critically review several selected pharmacologic strategies.     

Desipramine plasma levels and response in elderly melancholic patients

The relationship of response and plasma desipramine concentrations was examined in elderly depressed patients to determine whether they were more sensitive to the antidepressant effects of the drug and whether they would respond at lower plasma concentrations than younger patients. Twenty-five inpatients over the age of 60, who met criteria for major depression with melancholia, were unipolar, were not delusional, were without active medical illness or definite brain disease, and were still depressed after 1 week of hospitalization off psychotropic drugs, were treated with desipramine (2.5 mg/kg) for 3 weeks. Of the 18 patients completing the drug trial, six responded and 12 did not. Desipramine levels of responders (median, 126 ng/ml) were higher than those of nonresponders (median, 81 ng/ml; Mann-Whitney test, p less than 0.05). The threshold for response was the same as the threshold (115 ng/ml) observed in 31 nondelusional melancholic patients under the age of 60 treated in a similar manner with desipramine. Among elderly patients with levels above 115 ng/ml, four of five responded, and below this level, two of 13 responded (Fisher's exact test, p less than 0.025). Five patients not responding to the initial 3-week trial responded when desipramine was increased and the plasma level rose above 115 ng/ml. The data indicate that elderly melancholic patients to not respond to lower desipramine plasma concentrations and that therapeutic levels are similar to those for younger melancholic patients. The doses of desipramine needed to reach these levels were also similar to those required in younger patients.     

The Expression of VGF is Reduced in Leukocytes of Depressed Patients and it is Restored by Effective Antidepressant Treatment

Major depression is a disease characterized by an inability of neuronal systems to show appropriate adaptive plasticity especially under challenging conditions, such as stress. Conversely, pharmacological intervention may normalize such defects through the modulation of factors that might act in concert for the functional recovery of depressed patients, like the neuropeptide VGF, which has previously shown to possess antidepressant like activity. We analyzed VGF mRNA levels in the brain of rodents exposed to stress or treated with antidepressant drugs. In addition, we assessed VGF expression in leukocytes obtained from 25 drug-free depressed patients before and during antidepressant treatment. We found a persistent reduction of VGF expression after exposure to prenatal stress and an upregulation of its levels following chronic treatment with different antidepressant drugs. Moreover, VGF mRNA levels were significantly reduced in drug-free depressed patients, as compared with controls, and were modulated in response to effective antidepressant treatment. Our data provide further support to the role of VGF in mood disorders and suggest that VGF could be a more specific biomarker for treatment responsiveness.     

Cerebral laterality and depression: relations of perceptual asymmetry to outcome of treatment with tricyclic antidepressants

The relationship of cerebral laterality to outcome of treatment with antidepressants was examined by comparing perceptual asymmetry in subgroups of depressed patients formed on the basis of clinical response to a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI). Perceptual asymmetries of 63 unmedicated depressed patients were assessed for verbal and nonverbal tasks, using dichotic listening and visual half-field methods, and retests were obtained on 49 patients after about 6 weeks of treatment. There were significant differences between TCA responders and TCA nonresponders in dichotic listening and visual field asymmetries. Differences in perceptual asymmetry were specific to TCAs, in that no comparable differences existed between MAOI responders and MAOI nonresponders. Although perceptual accuracy improved following successful TCA treatment, abnormal perceptual asymmetries in TCA responders were present before and after treatment and may thereby represent state-independent characteristics.     

A multi-centre general practitioner assessment of butriptyline hydrochloride ('Evadyne').

A multi-centre open study in general practice was carried out to assess the efficacy of and incidence of side-effects with the tricyclic antidepressant, butriptyline. Of a series of 153 patients with non-psychotic depression, with or without anxiety, 105 (69%) were judged as having a good or fair response to treatment with 75 mg to 150 mg butriptyline daily. Side-effects of an anticholinergic nature were seen in 13.7% of patients, but the incidence decreased to less than 4% in the 101 patients receiving treatment for over 7 weeks.