Jan A. Bruijn

Motor activity and autonomic cardiac functioning in major depressive disorder

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.

Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (Org 3770).

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.

Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression

Biopterin, neopterin and the large neutral amino acids (LNAA), i.e. phenylalanine, tyrosine, tryptophan, isoleucine, leucine and valine were measured in plasma of 20 severely depressed inpatients before and after a course of electroconvulsive therapy (ECT). These patients showed a significantly lower plasma biopterin concentration at baseline in comparison with healthy controls. After treatment an increase in biopterin was found, which was statistically significant in the depressed patients with psychotic features. The plasma phenylalanine-tyrosine ratio, which previously increased, normalised after ECT. Mean tryptophan concentration was lower in depressed patients than in normal controls. The patients who responded to ECT showed an increase in the tryptophan concentration and its ratio (tryptophan/LNAA) after treatment. Our results suggest that ECT increases biopterin, which probably results in synthesis of amino acids, especially tyrosine. Furthermore, ECT seems to increase cerebral tryptophan availability because of less tryptophan catabolism parallel with biopterin activation. More research is required to see if biopterin could be useful as a biological marker for the depressive state in this subgroup of patients, because this compound seems to play an important role in the etiology and treatment of depression.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

Wijkstra J, Burger H, van den Broek WW, Birkenhäger TK, Janzing JGE, Boks MPM, Bruijn JA, van der Loos MLM, Breteler LMT, Ramaekers GMGI, Verkes RJ, Nolen WA. Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

CPT performance in major depressive disorder before and after treatment with imipramine or fluvoxamine

Numerous neuropsychological studies have reported deficits in cognitive and attentional functioning in depressed patients. However, there are limited data available about unmedicated depressed patients and the effects of antidepressant treatment on attentional performance. In this study, a Continuous Performance Test (CPT) was employed to evaluate the attentional performance of depressed inpatients during a drugfree period (n = 52) in comparison to healthy control subjects (n = 73). After 4 weeks of double-blind treatment with imipramine (TCA) or fluvoxamine (SSRI) at adequate plasma levels the CPT performance was studied again. We found that the unmedicated patients had a significantly impaired performance on all CPT parameters (reaction time, omission errors and commission errors) in comparison to the controls. None of the CPT parameters correlated with the severity of the depression or the level of psychomotor retardation. However, the CPT performance in the patient group was significantly related to subjective mood state (depression, tension). Double-blind treatment with imipramine or fluvoxamine resulted in an improvement of the CPT performance. In the imipramine treatment group the mean reaction time decreased significantly, and after treatment with fluvoxamine a significant decrease of the mean reaction time and the number of omission errors was detected. Both antidepressants induced a significant improvement of clinical state, but we did not find a relationship between the altered CPT performance and the changes on the clinical scales. Future studies should investigate other mechanisms underlying the improved attentional performance after treatment.

24-Hour motor activity after treatment with imipramine or fluvoxamine in major depressive disorder

Psychomotor dysfunction in depression is related to alterations in the 24-h pattern of motor activity. After antidepressant treatment the diurnal pattern may be changed due to improvement of clinical state or pharmacological actions. The purpose of this study was to evaluate in 52 depressed in-patients the effects of imipramine (tricyclic antidepressant) and fluvoxamine (SSRI) on the 24-h motor activity. Motor activity was monitored by wrist-actigraphy during a medication-free period and after 4 weeks of treatment. Clinical improvement was not different after imipramine or fluvoxamine treatment. The Hamilton depression score decreased in patients treated with imipramine, as well as in patients treated with fluvoxamine. The clinical retardation score was also reduced in both treatment groups. However, patients treated with imipramine showed higher motor activity levels during the wake period in comparison to the medication-free period, and more fragmentation of motor activity during sleep. Treatment with fluvoxamine did not result in alterations in the 24-h pattern of motor activity. The improvement of depressive mood and retardation seems to play a minor role in the change of the pattern of motor activity after imipramine.

Anxiety and autonomic regulation in major depressive disorder: an exploratory study

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.

A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients

ObjectiveTo compare the efficacy of imipramine and fluvoxamine in inpatients from two centers suffering from a depressive disorder according to DSM IV criteria.MethodsThe study included 141 patients with a depressive disorder according to DSM IV criteria. After a drug-free and placebo run-in period of 1 week, patients were randomized to imipramine or fluvoxamine; doses of both drugs were adjusted to a predefined target blood level. Efficacy was evaluated 4 weeks after attaining predefined adequate plasma level.ResultsThe mean age of the study group (47 males, 94 females) was 51.8 (range 19–65) years. Of these 141 patients, 56 had episode duration longer than 1 year, 48 had mood congruent psychotic features, and 138 patients received medication. Seven patients did not complete the medication trial. The total number of patients using concurrent medication was 12/138 (8.6%). On the primary outcome criteria patients on imipramine improved significantly better on the change of illness severity score of the CGI (χ2 exact trend test=4.089, df=1, P=0.048). There was no significant difference in 50% or more reduction on the HRSD, the other primary outcome criterion. On the secondary outcome criteria the mean reduction of the HRSD scores was significantly larger in the imipramine group than in the fluvoxamine group (mean difference=3.1, standard error (SE)=1.4, t=2.15, df=136, P=0.033). There was no significant difference in the number of patients with an HRSD ≤7 at the final evaluation.ConclusionsIn depressed inpatients imipramine is more efficacious than fluvoxamine. Both drugs were well tolerated by all patients.

Effect of Antidepressant Medication Resistance on Short-term Response to Electroconvulsive Therapy

Abstract: 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 ≤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.

Treatment of mood-congruent psychotic depression with imipramine

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.