Juha Markkula

Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635

Serotonin (5-HT) is involved in the pathophysiology of major depressive disorder (MDD). Among the numerous serotonergic receptors, the 5-HT1A receptor subtype is of interest because of its involvement in cognition, hippocampal neurogenesis, and mechanism of action of antidepressant drugs. Previous imaging studies have suggested altered availability of 5-HT1A receptors in MDD but prior antidepressant medication and chronicity of the illness may confound the interpretation. We examined 21 drug-naive primary-care patients with MDD using positron emission tomography (PET) imaging with [carbonyl-11C]WAY-100635, a radioligand for 5-HT1A receptors, along with 15 healthy control subjects. Binding to receptors was assessed both regionally and at voxel level with the binding potential (BP) that was estimated using arterial blood input. Compared with healthy controls, the BP of [carbonyl-11C]WAY-100635 was reduced in patients with MDD in most brain regions, ranging from -9% to -25%. Voxel-level analysis confirmed this finding by showing a widespread reduction of [carbonyl-11C]WAY-100635 BP. No statistically significant associations were observed between BP and total HAMD scores in the patients, but lower BP was associated with higher likelihood of insomnia. This study demonstrated a widespread reduction in the availability of serotonin 5-HT1A receptors in a relatively large sample of drug-naive primary-care patients with MDD, suggesting the involvement of this receptor subtype in the pathophysiology of the illness. Lack of correlation with overall severity of the illness may relate to a largely trait-like nature of this abnormality in depressive disorders.

Short-Term Psychodynamic Psychotherapy and Fluoxetine in Major Depressive Disorder: A Randomized Comparative Study

Background: There are few studies comparing the efficacy of short-term psychodynamic psychotherapy (STPP) and pharmacotherapy in major depressive disorder. We conducted a comparative study on the efficacy of STPP versus fluoxetine treatment in patients with major depressive disorder in a primary care setting. Methods: Fifty-one patients with major depressive disorder (DSM-IV) of mild or moderate severity were recruited through occupational health services providing primary health care. Patients were randomized to receive either STPP (1 session/week) or fluoxetine treatment (20–40 mg/day) for 16 weeks. The outcome measures included the Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (BDI), and the Social and Occupational Functioning Assessment Scale (SOFAS). Results: Intent-to-treat analyses indicated that both treatments were highly effective in reducing the HDRS (p < 0.0001) and BDI (p < 0.0001) scores, as well as in improving functional ability (SOFAS; p < 0.0001), with no statistically significant differences between the treatments. Of those 40 subjects who completed the follow-up, 57% in the psychotherapy group and 68% in the fluoxetine group showed full remission (HDRS ≤7) after 4 months. Conclusions: Both STPP and pharmacological treatment with fluoxetine are effective in reducing symptoms and in improving functional ability of primary care patients with mild or moderate depression. This study suggests no marked differences in the therapeutic effects of these two treatment forms in a primary care setting.

Research Letter:Psychotherapy increases brain serotonin 5-HT1A receptors in patients with major depressive disorder

The serotonin 5-HT1A receptor system is implicated in the pathophysiology of major depressive disorder (MDD) (Stockmeier, 2003) and serotonergic medications are currently widely used in the treatment of MDD. Previous molecular imaging studies in patients with MDD have provided evidence of a widespread decrease in the density of serotonin 5-HT1A receptors in the disease (Drevets et al. 1999; Sargent et al. 2000 ; Bhagwagar et al. 2004 ; Meltzer et al. 2004 ; Hirvonen et al. 2008, but see Parsey et al. 2006 for opposite results). Psychotherapy usually results in clinically identical outcomes with medication in the treatment of patients with mild to moderate MDD (Ebmeier et al. 2006). However, nothing is known about the molecular mechanisms mediating the effects of psychotherapy. To test and compare the effects of fluoxetine medication and a brief psychotherapy on 5-HT1A receptor density in patients with MDD we conducted a randomized comparative study. Positron emission tomography (PET) scanning with the 5-HT1A radiotracer [carbonyl-C]WAY-100635 was performed before and after the intervention to measure alterations in 5-HT1A receptor binding.

Striatal dopamine D2 receptors in medication-naive patients with major depressive disorder as assessed with [11C]raclopride PET

RationaleAmong other monoamine neurotransmitters, dopamine is implicated in the pathophysiology of major depression. Experimental studies suggest the involvement of the mesolimbic dopamine system in the mechanism of action of antidepressant drugs. Previous in vivo imaging studies have studied striatal dopamine D2 receptor availability in depression but the results are equivocal thus far.ObjectiveTo study the striatal and thalamic dopamine D2 receptor availability in drug-naive patients with major depression was the aim of this study.Materials and methodsCaudate, putamen, and thalamic dopamine D2 receptor availability was estimated using positron emission tomography and [11C]raclopride in 25 treatment-seeking drug-free patients (of whom 24 were drug-naive) with major depression (primary care patients) as well as in 19 demographically similar healthy control subjects. Receptor availability was expressed as the binding potential (BPND), and analyses were carried out based on both regional and voxel-level BPND estimates.ResultsNo statistically significant differences in [11C]raclopride BPND were observed between the groups either in the caudate nucleus (+1.7%, CI −4.8% to +8.3%), putamen (−1.0%, CI −7.2% to 5.1%), thalamus (−2.4%, CI −8.7% to 4.0%), or ventral striatum (−3.8%, CI −9.3% to +1.6%). In the patients, depressive symptoms were not associated with [11C]raclopride BPND in any region.ConclusionsThe findings in this sample of treatment-seeking, drug-naive and predominantly first-episode patients with major depression do not support the involvement of striatal dopamine D2 receptors in the pathophysiology of the illness, but do not exclude the potential importance of dopaminergic mechanisms in antidepressant drug action.

Effects of antidepressant drug treatment and psychotherapy on striatal and thalamic dopamine D2/3 receptors in major depressive disorder studied with [11c]raclopride PET

Antidepressant drug treatment and psychotherapy are both effective in treating major depression, but there are no published studies comparing the effects of these two treatments on the dopaminergic neurotransmitter system in major depression. We conducted a randomized comparative study on the effects of fluoxetine medication and short-term psychodynamic psychotherapy on striatal and thalamic dopamine D2/3 receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D2/3 receptor binding was quantified before and after treatment as the binding potential (BPND) using [11C]raclopride and 3D positron emission tomography. Both treatments were clinically effective in treating major depression, as shown by substantial decreases in symptom ratings. Yet, there were no effects on D2/3 receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [11C]raclopride BPND in lateral thalamus (+7.74%, p = 0.002) but this increase was not correlated with clinical improvement. In conclusion, this preliminary study does not support the involvement of ventral dopaminergic neurotransmission in the antidepressant effects of fluoxetine or psychodynamic psychotherapy. The effects of fluoxetine on thalamic dopamine systems need to be further explored.

A population-based survey of sleep disturbances in middle-aged women – Associations with health, health related quality of life and health behavior

OBJECTIVE To evaluate the prevalence of sleep disturbances and the contributing factors in middle-aged women. METHODS In a cross-sectional design of the long-term, prospective follow-up study project of 1278 families from a random population sample, the mothers of 15 year-olds were asked to fill in a questionnaire about sleep, health, health related quality of life, and health behavior. RESULTS Quality of sleep was reported by 32% of women as good, 43% quite good, 12% average, 10% quite poor and 3% as poor. The most frequent sleep disturbance was awakenings in the night, which 60% of the women experienced at least once a week. Difficulty falling asleep and waking too early in the morning were reported as a weekly occurrence by 16% and 20%, respectively. Morning sleepiness was experienced by 42% and daytime sleepiness by 32%. Chronic diseases and use of medications was associated with various sleep disturbances. Both somatic and mental symptoms increased the risk for sleep disturbances. CONCLUSIONS Almost one-quarter of middle-aged women is dissatisfied with their quality of sleep. Women who have chronic disease or use of medications for basic diseases often suffer from sleep disturbance, which is also associated with the health related quality of life. Further analysis of the risk factors is needed to improve the sleep health of middle-aged women.

Mirtazapine-induced restless legs

Two cases of restless legs syndrome in association with mirtazapine treatment of 5–6 weeks are presented. Rather than akathisia related to serotonine reuptake inhibitors, which usually emerges during the first weeks of treatment, our cases resemble previously described mianserin‐induced RLS cases. This suggests that although blockade of 5‐HT2 receptors by mirtazapine may be protective against acute akathisia, it does not protect against slowly developing restless legs syndrome similar to that induced by mianserin.

Recurrent CSPs after Transcranial Magnetic Stimulation of Motor Cortex in Restless Legs Syndrome

Aims. The aim of this study was to investigate the motor control and central silent period (CSP) in restless legs syndrome (RLS). Methods. Transcranial magnetic stimulation was focused on the dominant and nondominant hemispheric areas of motor cortex in six subjects with RLS and six controls. The responses were recorded on the contralateral abductor digiti minimi (ADM) and tibialis anterior (TA) muscles with intramuscular needle electrodes. Results. No significant differences were found in the motor conduction or central motor conduction time, in the latency, or in the duration of the CSPs between or within the groups, but multiple CSPs were observed in both groups. The number of the CSPs was significantly higher in both ADMs and in the dominant TA (P ≤ 0.01) in the RLS group compared to the controls. Conclusion. Descending motor pathways functioned correctly in both groups. The occurrence of the recurrent CSPs predominantly in the RLS group could be a sign of a change of function in the inhibitory control system. Further research is needed to clarify the role of the intramuscular recording technique and especially the role of the subcortical generators in the feedback regulation of the central nervous system in RLS.

Personality traits and recovery from major depressive disorder

Objective: To study the correlation of personality traits measured by the Temperament and Character Inventory (TCI) with the prognosis of major depressive disorder in patients treated with either fluoxetine or short-term psychodynamic psychotherapy in a randomized comparative study. Method: 35 patients with DSM IV-defined major depressive disorder of mild or moderate severity were randomized to receive either short-term psychodynamic psychotherapy or fluoxetine treatment for 16 weeks. Prior to beginning of the therapy, patients were assessed with TCI. The Hamilton Depression Rating Scale (HDRS) was used as the outcome measure completed at the baseline and follow-up at 4 months. Results: In the combined group (n=35), Harm Avoidance was associated with the severity of the depression measured by the HDRS at the baseline (P=0.01) and baseline Self-Directedness with the HDRS at 4 months follow-up (P=0.03). In the fluoxetine treatment group, Reward Dependence (P=0.03), Self-Directedness (P=0.01) and Cooperativeness (P=0.02) at the baseline associated with HDRS at 4 months follow-up. No statistically significant associations between personality traits and depression scores at the follow-up were found in the patients treated with psychotherapy. Conclusion: In this whole cohort of depressive patients, baseline high Self-Directedness predicted higher depression scores after 4 months of treatment. In the fluoxetine treatment group, subjects with high baseline Reward Dependence, Self-Directedness or Cooperativeness were likely more severely depressed at the 4 months follow-up. We suggest that associations between personality traits and remaining depressive symptoms after 4 months treatment with fluoxetine could be caused by the potential differences in the placebo effect.

On the relationship of atypical and low-dose conventional antipsychotics with akathisia in a clinical patient population

Metabolic side-effects of atypical antipsychotics have led to concern about their relative safety compared with low doses of conventional neuroleptics. Akathisia is an often misdiagnosed side-effect, which leads to non-compliance and sometimes even exacerbation of psychosis or suicidal behaviour. In fact, little is known about the differences between antipsychotic drugs in clinical practice, since only as few as 20% of patients may be eligible for studies comparing antipsychotic medications with each other. The aim of this study was to find out if the use of conventional antipsychotics is associated with an increased risk of akathisia (compared with atypical antipsychotics) even when low doses of conventional antipsychotics are used. The Barnes Akathisia Rating Scale was used to evaluate akathisia in 100 outpatients on antipsychotic medication. Conventional antipsychotics were associated with an increased risk of akathisia compared with atypical antipsychotics, although the chlorpromazine equivalent doses of conventional antipsychotics were lower than those of the atypicals. An additional akathisia-provoking effect of SSRIs could not be ruled out. The results suggest favouring atypical antipsychotic medication in patients who may easily develop akathisia.