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To investigate the effects of antidepressants on glucose-insulin homeostasis, we provided homogenous situation and performed standard procedures to assess the interactions of antidepressants and glucose regulation during hospitalization.Twenty-three non-diabetic depressed males were recruited and assigned to two groups based on the antidepressants received (maprotiline n=11, fluoxetine n=12). The severity of depression was evaluated using a 21-item Hamilton depression rating scale (HAM-D). Before and after the 4-week treatment, participants underwent 75-g oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (SI), glucose effectiveness (SG), acute insulin response (AIR), and disposition index (DI) were estimated using minimal model method.The HAM-D scores were reduced significantly (P0.005) after antidepressant treatment. Following maprotiline treatment, the body weight and BMI were significantly increased (P=0.02). Individuals treated with maprotiline displayed a significantly increased AIR (3239+/-682 vs. 4698+/-597 pmol; P=0.04) during the FSIGT.The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course.The results suggest that the beta-cell function is hyperbolic in order to offset the insulin resistance following maprotiline treatment. Our findings imply that norepinephrine reuptake inhibitor (NRI) antidepressants might attenuate insulin sensitivity.

Background Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method. Methods We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40 mg/d. Results We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40 mg/day was equivalent to paroxetine dosage of 34.0 mg/day, agomelatine 53.2 mg/day, amitriptyline, 122.3 mg/day, bupropion 348.5 mg/day, clomipramine 116.1 mg/day, desipramine 196.3 mg/day, dothiepin 154.8 mg/day, doxepin 140.1 mg/day, escitalopram 18.0 mg/day, fluvoxamine 143.3 mg/day, imipramine 137.2 mg/day, lofepramine 250.2 mg/day, maprotiline 118.0 mg/day, mianserin, 101.1 mg/day, mirtazapine 50.9 mg/day, moclobemide 575.2 mg/day, nefazodone 535.2 mg/day, nortriptyline 100.9 mg/day, reboxetine 11.5 mg/day, sertraline 98.5 mg/day, trazodone 401.4 mg/day, and venlafaxine 149.4 mg/day. Sensitivity analyses corroborated the results except for doxepin. Limitations The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants. Conclusions Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research.

Background: Cloninger’s theory of personality, including 4 temperament dimensions and 3 character dimensions, is one of the most noteworthy theories in recent years. Several studies have explored temperament dimensions as a predictor of response to antidepressant treatments in major depression, but these have provided inconsistent results. The present study explored temperament as well as character dimensions, as measured by the Temperament and Character Inventory (TCI), as possible predictors of response to maprotiline, the most-widely prescribed antidepressant in Japan. Methods: 86 consecutive patients with major depression underwent a 16-week open trial of maprotiline. They filled out the TCI at baseline, and were followed up at weeks 8 and 16 by using the Hamilton Rating Scale for Depression. Results: Hierarchial logistic regression analyses demonstrated that response to maprotiline was significantly predicted by the cooperativeness score at the 8-week outcome assessment, and by the self-directedness score at the 16-week outcome assessment, after controlling the possible effects of clinical variables on the response. There was no evidence that either temperament dimensions or their 2-way interactions significantly predicted the response. Limitations: Large replication studies with other antidepressants are needed for generalizing the results in this study. Conclusions: The results in this study regarding temperament dimensions seem consistent with findings in previous studies, which are, as a whole, inconsistent with each other. It is suggested that character dimensions (particularly cooperativeness and self-directedness), rather than temperament dimensions, may be important predictors of response to antidepressants. Antidepressants may differ in the personality configurations that predict optimal responses.

The results of the meta-analysis of studies comparing the efficacy of moclobemide, imipramine and so-called sedative antidepressants (amitriptyline, mianserin and maprotiline) in 2416 patients are described. The results demonstrated that in agitated-anxious depressive patients (defined by HAMD factor score or HAMD item 9) a nonsedative, reversible MAO-A inhibitor moclobemide has about equal efficacy as imipramine or sedative antidepressants. All antidepressants were clearly superior to placebo, irrespective of the outcome measures applied (> 50% HAMD decrease, CGI improvement). The efficacy of antidepressants in agitated patients was unrelated to the severity of agitation and did not appear to be inferior to the efficacy in nonagitated patients. Comedication with benzodiazepines had no impact on overall efficacy of either moclobemide or other antidepressants in this patient population. Previous treatment with antidepressants, however, always negatively influenced the outcome with trial drugs, e.g., reduced their efficacy. Placebo response in agitated depressives appeared generally to be low (20–30%) and was clearly reduced with increased severity of agitation, irrespectively of how the agitation was defined.

The predictive value of eight domains or sets of variables including sociodemographic aspects, premorbid history, symptomatology, personality, social and diagnostic data are evaluated in depressed outpatients with a Hamilton Rating Scale for Depression (HRSD) score of at least 14. Patients were treated using a three-phase sequential treatment strategy. Of the 119 patients, 88 completed the trial. The HRSD-score at the end of phases I, II or III was used as an outcome measure. Patients with an initially high HRSD-score and an obsessive-compulsive personality had a greater chance of recovery, while patients with somatization and a passive-aggressive personality had less of a chance of recovery. Variables involving psychiatric history, premorbid history or symptomatology of the depression, were not significantly related to outcome. The endogenous/non-endogenous distinction was not a predictor of response.

Depressed outpatients (n = 51) resistant to treatment with maprotiline were treated in a blind, randomized, single-centre study, for 6 weeks with either the reversible and selective monoamine oxidase A-inhibitor (MAO-A-I), brofaromine or lithium addition to maprotiline. The Hamilton Rating Scale for Depression was scored by an independent rater before and after the 6 week treatment period. No significant differences in efficacy were found between the two treatment regimes. In the patients who completed the trial, brofaromine was well tolerated with the exception of insomnia. Anticholinergic effects as well as thyroid dysfunctions (17 out of 20) were more frequent in the maprotiline/lithium group.

The addition of benzodiazepine hypnotics to a treatment with tricyclic antidepressants has received little systematic study. In a double-blind placebo-controlled design, the effects on mood and on sleep of two benzodiazepine hypnotics (lormetazepam and flunitrazepam) were studied in patients with major depression who were also treated with maprotiline or nortriptyline. After 4 weeks of combined treatment, lormetazepam resulted in a significantly greater decrease in the score on the Hamilton Depression Subscale than placebo, while there was a non-significant trend in favour of lormetazepam in comparison with flunitrazepam. With respect to sleep EEGs, lormetazepam resulted in a significantly greater suppression of REM sleep. The differences between lormetazepam and flunitrazepam may be partly explained by the shorter half-live of lormetazepam.

A possible role for somatostatin in affective disorders is suggested by its low concentration in cerebrospinal fluid of patients with depression. Therefore, we studied the regional effects of antidepressant drugs and antimanic agents on somatostatin concentrations in rat brain. Repeated, but not acute, administration of clomipramine, a specific serotonin uptake inhibitor, caused a highly significant, widespread reduction in somatostatin levels. Somatostatin content was similarly reduced in the hypothalamus, and midbrain and thalamus following repeated administration of zimelidine, another specific serotonin uptake inhibitor. Repeated administration of either imipramine, maprotiline, mianserin, carbamazepine or zotepine were without effect on somatostatin levels. These results suggest that somatostatin in the brain might be involved in therapeutic effects of some of antidepressant drugs.

Platelet 5-HT levels and scores on the 17-item Hamilton Rating Scale for Depression (HRS) were studied in patients with unipolar depression before and after antidepressant treatment. Before treatment there were no differences in platelet 5-HT values or in HRS scores between patients who showed a good and a poor therapeutic response. Repeated administration of 5-HT uptake inhibitors (amitriptyline, clovoxamine, fluvoxamine) for 28 days markedly decreased platelet 5-HT levels. Chronic treatment with trazodone or maprotiline (weak inhibitors of platelet 5-HT uptake) produced no changes in platelet 5-HT levels. No significant correlation was observed between platelet 5-HT concentrations and the HRS scores before or during treatment. The findings suggest that the changes in platelet 5-HT levels after antidepressant treatment are mainly due to the effects of antidepressants on the 5-HT uptake system.

Background: No systematic study has been conducted to explore the relationship of dysfunctional parenting early in life, as measured by the Parental Bonding Instrument (PBI), to outcomes of depression, although a number of studies have related parenting behaviors to the development of depression in adulthood. Methods: The relationship between PBI scores and 4-month outcomes after treatment with antidepressants was explored in 60 outpatients with major depression, controlling for potentially confounding factors. Results: A multiple logistic regression analysis suggested that low levels of paternal care, unmarried condition, non-melancholic features, and a high isolation tendency were all factors that contributed to poor outcomes for depression. The predictive power of low paternal care was not influenced by levels of depression or neuroticism. Limitation: This study did not attempt to explore whether the effects of parenting of father and mother on outcomes for depression may differ between male and female subjects. Conclusion: The results suggest that low levels of paternal care may be an independent predictor of a poor response to treatment with adequate antidepressants.

Several concepts of minor depression in the sense of acute but less severe symptomatology than major depression have been proposed in the literature, but currently none of them is generally accepted. For the treatment of these conditions, only few recommendations based on empirical data are available. We conducted a randomized double-blind multicentre study in depressed outpatients comparing paroxetine and maprotiline in both patients with minor (n = 245) and major depression (n = 298). For the diagnosis, Research Diagnostic Criteria were used in a modified version. Two response criteria were applied: a reduction of 50% or more in total HAMD-17 scores from baseline (criterion 1), and a reduction of the HAMD-17 total score to 9 points or less (criterion 2). A completer and an endpoint analysis was performed. For patients with minor depression, remarkably high response rates were found for paroxetine (criterion 1: 90.9% completer, 82.1% endpoint; criterion 2: 89.1% completer, 82.4% endpoint) while the respective rates for maprotiline tended to be lower (criterion 1: 80.4% completer, 71.4% endpoint; criterion 2: 84.9% completer; 76.1% endpoint). Response rates in patients with major depression were for paroxetine: criterion 1: 74.3% completer, 62.8% endpoint; criterion 2: 76.4% completer, 65.2% endpoint; and for maprotiline: criterion 1:82.4% completer, 68.5% endpoint; criterion 2: 80.6% completer; 66.0% endpoint, which resembles rates reported from previous antidepressant trials. Both drugs were generally well tolerated. Though no placebo control was carried out, our results suggest that minor depression is a disorder that is very likely to respond to antidepressant pharmacotherapy with paroxetine, but also with maprotiline at a favourable risk/benefit ratio.

Patients treated with the norepinephrine uptake inhibitor maprotiline showed an opposite tendency between acute and chronic effect of EEG. Whereas the acute effect indicated a decrease upon EEG vigilance, the chronic effect indicated an increase. Under clomipramine which acts upon different transmitter systems in a complex, up to now not fully understood way, acute and chronic EEG effects could not be differentiated.

The aim of this study was to test the hypothesis of noradrenergic and serotoninergic depressive subtypes. For this purpose, the correlation between three variables was investigated: urinary 3-methoxy- 4-hydroxyphenylglycol (MHPG), dexamethasone suppression test (DST), and clinical response profiles to clomipramine and maprotiline, the effects of which are relatively selective on the uptake of noradrenalin (NA) and 5-hydroxytriptamine (5HT). Our results showed no correlation between these measures. Therefore, the hypothesis of two subtypes of depression was not supported. The only significant finding in this study was the obvious decrease in MHPG excretion during the antidepressant treatment in the group with high pretreatment MHPG.

The increasing proportion of elderly to the general population and the relatively high prevalence rate of depression in this age group justifies concern for specific clinical indications for antidepressant selection. Of the numerous agents that possess antidepressant activity, some have a more narrow therapeutic window for the old (lithium), while others may be more efficacious for the old than traditional tricyclics (stimulants and monoamine oxidase inhibitors). Stimulants and monoamine oxidase inhibitors require close monitoring to obviate complications, and this limits their use in this population. Prescription of the more common reuptake inhibitors in this age group can be based on consideration of efficacy and especially predictable incidence of side effects. Efficacy of all the reuptake inhibitors is essentially equivalent over 4 weeks, if the patient can tolerate treatment. Antidepressants with many side effects are, thus, less efficacious if we consider only whether the patient will be better 4 weeks after we start treatment since drop outs must be considered treatment failures for that particular treatment. Side effects are more clearly different among the antidepressants with demonstrably fewer cardiac effects (i.e. ECG changes, orthostatic hypotension) for buproprion, mianserin, nomifensine, and trazodone in the geriatric group compared to older agents such as amitriptyline and imipramine. Further, anticholinergic effects in the periphery (dry mouth, constipation, blurred vision, and urinary hesitancy) and centrally (confusion, sedation, decreased memory recall) are substantially less with several of the newer antidepressants: buproprion, maprotiline, nomifensine and trazodone.

Twenty patients suffering from endogenous depression were treated with maprotiline for 4 weeks. Blood samples were collected at weekly intervals and severity of depression assessed using the Hamilton Depression Rating Scale. No simple relationship between plasma maprotiline concentration and amelioration score was observed at week 3 ( r s =0.25) or week 4 ( r s =-0.05). No significant difference in plasma concentrations between responders and non-responders was observed at week 4. Maprotiline was effective as an antidepressant in some patients.

[3H]Yohimbine binding to platelet alpha 2-adrenoceptors was studied in depressed patients and healthy volunteers. Where possible platelet binding measurement was repeated in depressed patients following treatment. Bmax of [3H]yohimbine binding did not differ significantly between depressed patients and control subjects and did not change with treatment in depressed patients. KD was significantly lower in female depressed patients, particularly in those who were post-menopausal. Multivariate analysis showed significant effects on KD of depression, season of testing and assay protein concentration.

Subgroups of clinically defined responders and non-responders to clomipramine or maprotiline showed different electroencephalographic dynamics of vigilance, even before pharmacotherapy was initiated. Two hours after the first drug administration subgroup differences no longer existed. On the 21st day of medication we found a tendency towards re-establishing the pre-drug situation. Our findings lend support to the assumption of ‘distinct biochemical subtypes’ which, however, rather correspond to different stages of the pathophysiological process than represent invariant ‘traits’.

Twenty patients suffering from endogenous depression were treated with maprotiline for 4 weeks. Blood samples were collected at weekly intervals and severity of depression assessed using the Hamilton Depression Rating Scale. No simple relationship between plasma maprotiline concentration and amelioration score was observed at week 3 (rs = 0.25) or week 4 (rs = -0.05). No significant difference in plasma concentrations between responders and non-responders was observed at week 4. Maprotiline was effective as an antidepressant in some patients.