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CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal-Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal-Wallis tests, P>or=0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, eta(2)=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations.

Objective: It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone., Method: In a multi-center RCT, 122 patients (18-65 years) with DSM-IV-TR psychotic major depression and HAM-D-17 > or = 18 were randomized to 7 weeks imipramine (plasma-levels 200-300 microg/l), venlafaxine (375 mg/day) or venlafaxine-quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM-D-17. Secondary outcomes were response on CGI and remission (HAM-D-17)., Results: Venlafaxine-quetiapine was more effective than venlafaxine with no significant differences between venlafaxine-quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern., Conclusion: That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine-quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.

The inactivation and clearance of the tricyclic antidepressant imipramine is dependent on CYP2D6 activity. First, CYP2C19 converts imipramine into the active metabolite desipramine, which is then inactivated by CYP2D6. This retrospective single center study aimed to prove whether CYP2C19 and ample CYP2D6 genotyping (taking into consideration four null alleles and three decreased-activity alleles) could be used to predict imipramine and desipramine plasma concentrations in depressed patients, and whether genotype-based drug dose recommendations might assist in the early management of imipramine pharmacotherapy. In 181 subjects with major depressive disorder, drug doses were recorded, imipramine and desipramine plasma concentrations were monitored and CYP2C19 (*2) and CYP2D6 genotype (*3, *4, *5, *6, *9, *10, *41 and gene duplication) were obtained, yielding graded allele-specific CYP2D6 patient groups. Desipramine and imipramine+desipramine plasma concentration per drug dose unit, imipramine dose at steady state, and imipramine dose requirement significantly depended on CYP2D6 genotype (Kruskal-Wallis test, P<0.0001). Mean (+/-s.d.) drug dose requirements were 131 (+/-109), 155 (+/-70), 217 (+/-95), 245 (+/-125), 326 (+/-213), and 509 (+/-292) mg imipramine/day in carriers of 0, 0.5, 1, 1.5, 2, and >2 active CYP2D6 genes, respectively. Our protocol for CYP2D6 genotyping will thus importantly aid in the prediction of imipramine metabolism, allowing for the use of an adjusted starting dose and faster achievement of predefined imipramine+desipramine plasma levels in all genetic patient subgroups. Therefore, therapeutic efficacy and efficiency may be improved, the number of adverse drug reactions decreased, and hospital stay reduced.

Background: There is still uncertainty regarding the best treatment optionfor depressed inpatients and the best strategy to follow if patient response is insufficient., Aim: To compare the efficacy of imipramine and fluvoxamine in depressed inpatients who subsequently received lithium supplement in case of poor response., Method: After a drug-free period and four days of placebo use, patients were randomised either to imipramine or to fluvoxamine (phase 1); the antidepressant dosage was fixed according to a predetermined plasma level. The efficacy of the antidepressant was evaluated four weeks after the predetermined plasma level had been attained. If patient response was inadequate, the antidepressant was augmented with lithium (phase 2). Patient response to the lithium addition was evaluated three weeks after an adequate lithium level had been attained., Results: The study involved 138 inpatients. At the end of phase 1, imipramine was found to be superior tofluvoxamine according to the Clinical Global Impression of Improvement. Remission was achieved by 6 (23%) patients on imipramine and by 10 (15%) patients on fluvoxamine; this difference was not statistically significant. At the end of phase 2, 41 (9%) patients on imipramine and 27 (40%) patients on fluvoxamine achieved remission, this significant difference demonstrating the superiority of the imipramine strategy., Conclusion: Imipramine with subsequent lithium addition is superior to a similar strategy with fluvoxamine.

Background: Most studies report a poor response of psychotic depressed patients to treatment with a tricyclic antidepressant alone compared to combined treatment with an antipsychotic preparation and compared to non-psychotic depressed patients. However, the issue of optimal treatment of psychotic depressed patients has not been resolved as yet. Previously, we reported a significant difference in response to mirtazapine compared to imipramine in a randomised, double-blind, fixed-blood-level study with in-patients with major depression. In the current study we focus on the treatment response to imipramine in a group of patients with psychotic depression and compare this to patients who manifest no psychotic features. Our aim in presenting these findings was to contribute to the discussion on the optimal treatment of psychotic depressed patients., Methods: Fifty-two patients with a unipolar major depression (DSM-IIIR), comprising 15 patients with mood-congruent psychotic features and 37 patients with no psychotic features, were commenced on treatment with imipramine after a drug-free and placebo-washout period of 7 days. The dose of imipramine was adjusted for all patients to a predetermined blood level. The Hamilton (HRSD) and Montgomery-Asberg (MADRS) Depression Rating Scales were used to evaluate treatment response., Results: Of the 45 patients who completed the study, nine of the 13 psychotic patients (69.2%) and 14 of the 32 non-psychotic patients (43.8%) responded to treatment. The patients with psychotic features demonstrated a lower mean final HRSD score, together with a greater fall in MADRS score over time, compared to the non-psychotic group. Both these findings remained statistically significant after controlling for a number of possible confounding factors., Conclusions: These results demonstrate that, in this group of patients with mood-congruent psychotic depression, imipramine used on its own together with strict control of serum drug levels produced a high treatment response rate of 70%., Clinical Implications: If replicated, these findings suggest that imipramine with control of blood levels of medication may be a useful first-line treatment for depressed patients with mood-congruent psychotic features., Limitations: Our sample size was modest. This fact may caution against generalisation of the results.

Tricyclic antidepressants and more recent antidepressants are generally considered to have equivalent efficacy in the treatment of depression. After a previous report of a marked difference in the response to mirtazapine compared to imipramine, we report here an analysis of different symptom clusters. One hundred seven consecutive in-patients with major depression (Diagnostic and Statistical Manual III-R, DSM-III-R) and a Hamilton Rating Scale for Depression (HRS-D) score of 18 points or more were randomly assigned to double-blind treatment. Two and four weeks after predefined blood levels had been obtained, the severity of depression was assessed using the HRS-D. The mean dosages used were 235 mg/day of imipramine and 77 mg/day of mirtazapine, the latter being in excess of the 15-45 mg/day range currently advised. Total HRS-D scores and seven symptom clusters were analyzed in the 85 patients (79%) who were not receiving any co-medication. Imipramine was more effective against the clusters related to core symptoms of depression: "depression and guilt", "retardation", and "melancholia", respectively. Mirtazapine showed a biphasic response with regard to the clusters "sleep" and "anxiety/agitation", respectively, which consisted of a marked response after two weeks of predefined blood level, but with a waning of this effect at four weeks. Imipramine produced a more gradual response on these clusters, which was more pronounced at four weeks than with mirtazapine. Two aspects of the present study could be related to this finding: blood level control resulted in optimal treatment with imipramine but not mirtazapine, and - most importantly - the patients were not receiving any anxiolytic or hypnotic co-medication. These findings suggest that mirtazapine may have anxiolytic and sedative properties and fewer antidepressant properties than imipramine in severely depressed in-patients.

Background: The purpose of this study was to compare the overall effectiveness of 2 treatment strategies for inpatients with severe major depressive episode (DSM-III-R): (1) mirtazapine (phase 1) and subsequent lithium addition (phase 2) or (2) imipramine (phase 1) and subsequent lithium addition (phase 2). We previously reported the results of phase 1., Method: In phase 1, patients were randomly assigned to treatment with either mirtazapine or imipramine, and doses were adjusted to obtain predefined blood drug levels. Nonresponders had lithium added to the double-blind mirtazapine or imipramine medication. The dose was adjusted to obtain a blood lithium level of 0.5-1.0 mmol/L. Treatment effects were evaluated weekly by the Montgomery-Asberg Depression Rating Scale for up to 2 weeks on this blood lithium level., Results: Data for 100 patients were available for comparison of the 2 treatment strategies. 80 patients received no comedication. By the end of phase 2, 24 (48%) of 50 had responded to mirtazapine and 32 (64%) of 50 had responded to imipramine (intent-to-treat analysis). A survival analysis of the total patient group intent-to-treat showed a significant difference in favor of the treatment strategy with imipramine and subsequent lithium addition., Conclusion: Efficacy of imipramine and subsequent lithium addition for nonresponders is superior to the same treatment strategy with mirtazapine. This applies to the patient sample studied, which consisted of 100 severely depressed inpatients, 29 of whom were psychotically depressed. More serious side effects of imipramine, however, led to discontinuation of imipramine in 5 patients. No serious side effects were observed during the phase of lithium addition to either imipramine or mirtazapine. We, therefore, prefer to start treatment with imipramine and test for fixed blood drug levels, and, if necessary, add lithium. In the case of prohibitive side effects, patients are switched to a modern antidepressant such as mirtazapine, and, if necessary, lithium is added to this antidepressant.

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-levels study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of > or = 18 were selected. After a drug-free and a placebo-washout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of > or = 18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks' treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied.

Spectral analysis of fluctuations in heart rate (HR) and blood pressure (BP) was applied to assess sympathetic and parasympathetic cardiovascular control mechanisms in patients with unipolar affective disorder before and after treatment with imipramine (IMI) or mirtazapine (MIR). In a double-blind randomized study, 10 patients received treatment with IMI and 10 patients received treatment with MIR. Cardiovascular parameters were studied before and after 4 weeks of treatment: HR and BP (Finapres) were recorded continuously during supine rest (SR) and orthostatic challenge (OC; 60-degrees head-up tilting). During SR and OC, power spectra were calculated for HR and systolic BP. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.50 Hz). Before treatment, the depressed patients (N = 20) differed from age-matched controls (N = 20) only in their response to OC: the depressed patients showed more suppression of HR variability (both mid- and high-frequency band fluctuations), indicating stronger vagal inhibition, and a reduced increase of BP variability (mid-frequency band fluctuations), indicating reduced sympathetic activation. After 4 weeks of treatment, patients treated with either antidepressant drug showed significant changes of HR (increase) and HR variability (decrease) during SR and OC; the suppression of mid- and high-frequency fluctuations of HR was larger for IMI than for MIR. The increase in HR and decrease in HR variability may be attributed to the anticholinergic properties of IMI (strong) and MIR (weak), resulting in cardiac vagal inhibition. Whereas MIR had no effect on BP or BP variability, IMI specifically reduced mid-frequency band fluctuations of BP as the result of a suppression of central sympathetic activity. Our data confirm and extend previous observations on the presence of autonomic dysfunctions in unmedicated depressed patients: spectral analysis of HR and BP fluctuations suggested that both parasympathetic and sympathetic mechanisms are involved, specifically during OC. The preexisting autonomic cardiovascular dysfunctions were not normalized by antidepressant drugs. In fact, some of the components of the cardiovascular autonomic dysfunction were further aggravated, depending on the pharmacologic profile of the drug under investigation.

Two women, aged 51 and 65 years, with tricyclic-resistant depression (DSM-III-R) were treated with lithium addition. This is a valuable therapeutic alternative. Interactions and side effects should be closely monitored. Treatment response is possible in a short period of time (1 week), but recovery after lithium addition may also take a few weeks. It is not yet clear which patients will respond to lithium addition and in what way, and which will not. It is advisable to use lithium addition with adequate plasma lithium levels.

With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect (P = 0.38). The odds ratios were not homogenous across studies (P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy. [ABSTRACT FROM AUTHOR]