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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.

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.

Background: Depression can occur in patients with or without trait anxiety. Although it is assumed that assessment of defenses can be useful in planning biological treatment, no studies have confirmed this hypothesis. In this study we focus on the relation between trait anxiety and defensive functioning, and on the combined influence of these personality characteristics on response to antidepressants among inpatients with a major depressive episode., Methods: Major depressive episode was diagnosed using the Schedule for Affective Disorders and Schizophrenia (SADS) and the severity of the depression was measured with the Hamilton Rating Scale for Depression (HAM-D). The level of trait anxiety was assessed using a questionnaire with 34 questions pertaining to trait anxiety. The Defense Style Questionnaire (DSQ 88) was used to assess defensive functioning followed by a weighted overall defensive functioning score (ODF). Partial correlations and multiple regression analyses were used to analyze the data., Results: The final sample included 85 patients. A significant negative effect of trait anxiety by ODF (p: 0.000) was found on the outcome score, i.e. the combination of a high score on trait anxiety and a low score on the ODF resulted in a significantly higher final score on the HAM-D., Conclusions: The most important finding in this study is that the combination of a high level of trait anxiety and immature defensive functioning evidently had a negative effect on antidepressant treatment outcome., (Copyright 2009 S. Karger AG, Basel.)

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.

The purpose of the present study is to compare the efficacy of imipramine in the treatment of psychotic versus nonpsychotic depression. Previous studies report varying results of monotherapy with antidepressants in psychotic depression. Because psychotic depression is seriously underinvestigated, performing a post hoc analysis of randomized clinical trials consisting of both psychotic and nonpsychotic depressed patients may contribute to the discussion on the optimal treatment of depressed patients with mood-congruent psychotic features. A total of 112 patients diagnosed with major depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) (40 with psychotic depression and 82 without psychotic features) received treatment with imipramine for 6 weeks after a washout period of 7 days. Imipramine doses were adjusted to attain a predefined fixed plasma level. Treatment response was assessed with the Hamilton Rating Scale for Depression (HAM-D). A logistic regression analysis showed a significantly larger reduction in HAM-D score in the sample with psychotic features compared with the nonpsychotic sample (regression coefficient, -3.47; SE, 1.7; P = 0.04). According to the primary outcome criterion, that is, the change in HAM-D score, imipramine was significantly more effective in the sample with psychotic depression compared with the nonpsychotic depressed patients. The contradiction between our results and those of several previous studies may be due to the fixed plasma level dosing of imipramine refraining from concurrent psychotropic medication or limiting our patient sample to patients with mood-congruent psychotic features.

The efficacy of the addition of lithium to an established course of antidepressant treatment can be explained by a synergistic effect of the two drugs on central 5-HT neurotransmission. In the present study we investigated the effect of lithium addition on the 5-HT concentration in plasma and platelets and the concentration of 5-HIAA. Thirty-nine depressed inpatients who fulfilled the DSM-IV criteria for major depressive disorder and who did not respond to monotherapy with either imipramine or fluvoxamine participated in this study. Concentration of 5-HT in both plasma and platelets did not change significantly during lithium addition. The 5-HT ratio (plasma concentration/platelet concentration) shows a small non-significant increase after 3 weeks lithium addition. The mean concentration of 5-HIAA shows a significant increase during lithium addition; with no difference between the imipramine and the fluvoxamine sample. The increments in 5-HIAA concentration during lithium addition are indicative of an increased 5-HT turnover.

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: The aim of this study was to examine whether phenelzine is a suitable alternative to tranylcypromine in antidepressant-resistant depression., Method: A total of 77 severely depressed in-patients, meeting the DSM-IV criteria for major depressive disorder, who failed to respond to fixed plasma level treatment with either tricyclic antidepressants or fluvoxamine were withdrawn from psychotropic medication and included in a double-blind flexible-dose 5-week comparison of tranylcypromine and phenelzine., Results: Of the 77 patients, 67 (87%) completed the trial, of whom 35 (52%) responded. No significant differences in response between both drugs were observed. Seventeen (44%) of 39 patients responded to tranylcypromine and 18 (47%) of 38 to phenelzine (> or = 50% reduction in Hamilton Rating Scale for Depression [HAM-D] score). The mean reduction in HAM-D score was 10.4 +/- 8.3 for the tranylcypromine sample versus 8.3 +/- 8.4 for the phenelzine-treated patients. Only a few patients (10%) used concomitant psychotropic medication. A substantial number of patients experienced severe side effects, mainly dizziness, agitation, and insomnia; the incidence was the same in both samples (21%)., Conclusion: No difference in efficacy was observed between both monoamine oxidase inhibitors in a sample of patients with severe antidepressant-refractory depression. Phenelzine appears to be a suitable alternative to tranylcypromine.

This prospective study assessed the influence of resistance to antidepressant pharmacotherapy on the short-term response to subsequent electroconvulsive therapy (ECT). Previous research has shown that patients with medication resistance were less likely to respond to ECT. This finding may be applicable to the population of depressed inpatients in The Netherlands, where ECT is often preceded by several medication trials. Eighty-five patients (61 female and 24 male patients) with DSM-IV criteria for depressive disorder, both with and without mood congruent psychotic features, were included for analysis. Medication resistance was rated with the Antidepressant Treatment History Form. Medication resistance was predefined in accordance with the previous research in this field. When a reduction of at least 50% on the 17-item version of the Hamilton Rating Scale for Depression (HRSD) between pre- and post-ECT is used as response criterion, medication-resistant patients were equally likely to respond to subsequent ECT (30/48 = 82.5%) than patients without medication resistance (30/37 = 81.1%). Even when post-ECT HRSD score < or = 7 was used (full remission), there was no significant difference between medication-resistant patients (21/48 = 43.8%) and patients without medication resistance (15/37 = 40.5%). When potential confounding variables were taken into account, these differences remain nonsignificant. In contrast to earlier research, medication resistance does not influence short-term response to subsequent ECT and it can still be of considerable efficacy., (Copyright 2004 Lippincott Williams and Wilkins)

The effect of etomidate and alfentanil on heart rate, systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure was compared with etomidate and placebo during electroconvulsive therapy (ECT). We also studied the influence of alfentanil on seizure duration using both the cuff method and 2-lead electroencephalographs on the prevention of myoclonus induction by etomidate, on duration of apnea and on postictal agitation after ECT. We enrolled 21 consecutive patients in a prospective placebo-controlled, within patient blocked randomized study. Alfentanil significantly reduced heart rate, diastolic arterial pressure, and mean arterial pressure both before and after the stimulus. The increase in these variables during the convulsion was not affected, compared with placebo. Alfentanil had no effect on seizure duration. However, apnea duration was prolonged during the alfentanil sessions as compared with placebo (73 seconds). Alfentanil did not significantly reduce the occurrence of myoclonus after etomidate as compared with placebo, nor did postictal agitation after ECT appear more often with alfentanil. Alfentanil could be useful to reduce tachycardia and hypertension during ECT in high-risk patients without effects on seizure duration. Alfentanil itself has no proconvulsive effect in combination with etomidate.

Background: The daily pattern of motor activity and the autonomic cardiovascular regulation were studied in major depression to quantify changes in psychomotor function and autonomic cardiac functioning. Additionally, relationships between motor activity parameters, cardiovascular measures and specific clinical features were examined., Methods: Wrist-actigraphy was used to monitor 24-h motor activity for 67 unmedicated (unipolar) depressed inpatients and 64 control subjects. During supine rest, spectral analysis was applied to assess HR and SBP variability, a baroreflex sensitivity (BRS) index and the respiratory frequency, in addition to mean heart rate (HR) and blood pressure (BP) levels for the patient group and a second control group (N=51)., Results: The patients showed a lower motor activity level and a reduced fragmentation of motor activity during wake, and a higher motor activity level and a decreased immobility during sleep. The mean HR and DBP level and the respiratory frequency were higher in the patient group than in the control group, but no differences in HR and SBP variability or BRS were found. Furthermore, motor activity parameters and cardiovascular measures of the patients were related to agitation and retardation and overall, patients with lower motor activity levels demonstrated lower SBP levels., Conclusions: This study confirms that the 24-h pattern of motor activity is altered in unmedicated depressed inpatients, but limited evidence was found for an autonomic cardiac dysfunction. Within the patient group there were relationships between motor activity parameters, cardiovascular measures, and clinical features, but the underlying neurobiological pathways need to be further explored.

In this cross-sectional study we explored in 101 depressive in-patients (DSM III-R) the association between level of trait anxiety and variables that have been investigated previously to discern primary and secondary depression, respectively. Besides, we explored the influence of trait anxiety level on difference in treatment response to either imipramine or mirtazapine. Trait anxiety was measured interviewing a close relative of the patient using a questionnaire related to aspects of psychic anxiety and to aspects of somatic anxiety. The interviewer focussed on fluctuating anxiety symptoms without persistent mood disturbance during the patient's normal lifelong functioning before developing a depressed mood. We found no relation between trait anxiety level and treatment response to either imipramine or mirtazapine. The most important finding of this study is the significant differential response to the diazepam test: depressive patients with high trait anxiety showed, predominantly, a disappearance of depressive symptoms without sedation and depressive patients with low trait anxiety showed, predominantly, sedation without disappearance of depressive symptoms. The opposite response to the diazepam test in patients with a different history of trait anxiety in spite of similar depressive symptomatology suggests differences in underlying pathophysiologic mechanisms.

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.

A woman aged 56 had been treated at the age of 23 for a psychotic depression with vital characteristics in the context of a bipolar disorder. The treatment included electroconvulsive therapy (ECT). From the age of 47, she suffered relapses; drug treatment proved inadequate. For the last 3 years, ECT was administered, which resulted in a good condition. ECT is an effective treatment in patients with depression resistant to medication. However, in spite of continuation pharmacotherapy, the proportion of patients relapsing within 6 months after successful ECT is large. For these patients, continuation ECT may be an efficacious method.

Seven patients with major depression who developed seizure inhibition during a course of ECT, were given intravenous theophylline to increase seizure duration. Infusion of 100-200 mg of theophylline, administered slowly over several minutes approximately 30 min before seizure induction, was found to effectively and safely prolong seizure durations. In a total of 55 treatment sessions, no cardiovascular or other complications were seen. On one occasion, seizure duration was prolonged to 220 s.

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 and blood pressure was employed to explore sympathetic and parasympathetic cardiovascular control mechanisms in relation to trait anxiety in major depressive disorder Sixteen drug-free female depressed patients were divided into two groups: those who were high on trait anxiety (HTA, n = 9) and those who were normal or low on trait anxiety (LTA, n = 7). In patients and age-matched female controls (n = 10), heart rate (HR), blood pressure (BP; Finapres device) and respiration were recorded during a period of supine rest (10 min), orthostatic challenge (60 degrees head-up tilting, 8 min), and post-orthostatic supine rest (8 min). Power spectra were calculated over the last 4 min of these three situations for HR, systolic BP, as well as for respiration. 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). Patients did not differ from controls during supine rest. During orthostatic challenge, HTA patients showed significantly more HR increase and suppression of high-frequency fluctuations of HR (suggesting stronger vagal inhibition) in comparison with the controls; this effect was accompanied by a significant increase in respiratory frequency. Both patients groups did not show the normal increase in mid-frequency band fluctuations of BP during orthostatic challenge, indicating reduced sympathetic activation. Low-frequency fluctuations of HR, as well as respiratory frequency during post-orthostatic supine rest of the HTA patients were significantly increased versus controls. This exploratory study indicates that trait anxiety may be a relevant factor when evaluating parasympathetic and sympathetic dysbalances in the state of a major depressive disorder.

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.

To investigate the possible differential sensitivity of hydrocortisone (HCO) on immunoglobulin (Ig) production in depression in relation to endogenous cortisol levels, blood was obtained at 8 AM and 4 PM from 10 inpatients with major depression according to DSM-III-R criteria and 10 age- and sex-matched healthy subjects. Peripheral blood lymphocytes were cultured in the presence of graded concentrations (10(-9)-10(-5) M) of HCO to study the effect on immunoglobulin (IgG and IgM) synthesis. In addition, peripheral blood lymphocytes were cultured in the presence of pokeweed mitogen (PWM) to study any additional effect of graded concentrations of HCO (10(-9)-10(-5) M) on IgG and IgM synthesis. Mean plasma cortisol levels at both time points were higher in patients compared to controls. HCO--preferentially at concentrations of 10(-8)-10(-6) molar--stimulated IgG and IgM production in controls, except for IgM production in the 8 AM samples, when the cells were cultured in the absence of PWM. Under these culture conditions, HCO stimulated IgG but not IgM synthesis in depressed patients. PWM-driven IgG and IgM synthesis in controls was stimulated by HCO in both the 8 AM and the 4 PM samples. In patients PWM driven IgG synthesis was stimulated by HCO in the 8 AM but not in the 4 PM samples. PWM-stimulated IgM synthesis was not augmented by HCO in depressed patients. We conclude that a differential sensitivity to the effects of HCO exists in in vitro IgG and IgM synthesis between depressed patients and controls. Furthermore, we suggest that immunocompetent cells of depressed patients possess corticosteroid-resistant properties.

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.