Dopamine D(1) receptor binding in the anterior cingulate cortex of patients with obsessive-compulsive disorder.

Functional neuroimaging studies in patients with obsessive-compulsive disorder (OCD) suggest there is a hyperactivation of the anterior cingulate cortex (ACC) during provocation of symptoms and conflict-inhibition tasks. Since dopamine, acting through D(1) receptors is suggested to modulate ACC activity, we hypothesised that there would be an altered D(1) binding potential (BP) in the ACC of OCD patients. Using [(11)C]-SCH23390 and positron emission tomography, we report significantly reduced D(1) BP in seven drug-free OCD patients compared with matched healthy controls. These findings suggest mesocortical dopamine inputs via D(1) receptors may play a role in the aetiology of OCD.

Dopamine D1 receptor binding in the striatum of patients with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder of unknown aetiology. Psychopharmacological studies have suggested a role for the neurotransmitter serotonin however further evidence for serotonin in the aetiology of OCD is conflicted. The authors used positron emission tomography (PET) to examine the binding of the dopamine D(1) receptor antagonist [(11)C]-SCH23390 to D(1) receptors in the striatum of drug-free OCD patients compared with healthy controls. METHODS: Seven drug-free patients (two drug naïve) with OCD and seven age, gender and education matched healthy controls underwent positron emission tomography with [(11)C]-SCH23390. Binding Potentials (BP) at D(1) receptors were calculated for the caudate nucleus and putamen. Correlations between BP values for basal ganglia regions and clinical measures were performed in OCD patients. RESULTS: The BP for [(11)C]-SCH23390 at D(1) receptors in OCD patients was significantly reduced in both caudate nucleus (0.59+/-0.06 vs 0.88+/-0.06, p<0.05) and putamen (0.89+/-0.06 vs 1.14+/-0.06, p<0.05) compared with healthy controls. No correlations were found between D(1) BP and symptom measures. LIMITATIONS: The main limitations of this study are the small sample size and the PET methodology which does not allow for disaggregation of Bmax and Kd values for D(1) receptor binding of [(11)C]-SCH23390. CONCLUSIONS: The finding of downregulation of D(1) receptors in the striatum of OCD patients suggests increased nigrostriatal dopaminergic drive in OCD. If confirmed, this finding provides support for trials of novel treatments in OCD based on dopaminergic system blockade.

Quetiapine augmentation in depressed patients with partial response to antidepressants.

OBJECTIVE: Clinical trials suggest between 30-50% of depressed patients have an inadequate outcome to antidepressant pharmacotherapy. Among the approaches to improve outcome has been augmentation with antipsychotic medications. We aim to investigate the efficacy and tolerability of augmentation with quetiapine in depressed patients with a partial response to antidepressants. METHODS: Patients with a Major Depressive Disorder (DSMIV) who had partial/no response to a stable dose of an Selective Serotonin Reuptake Inhibitors (SSRI)/SNRI were recruited. All patients received add-on quetiapine (200-600 mg nocte) in a 6-week trial. Outcome measures (HAMD, MADRS) were assessed at screening, baseline, weeks 1, 2, 4 and 6. Extrapyramidal symptoms (EPSEs) were assessed at baseline, weeks 2, 4 and 6. A neuropsychological battery of tests was administered at baseline, weeks 3 and 6. RESULTS: Nineteen patients entered the trial and 18 completed the trial per protocol. We report a rapid improvement in depression ratings over 6 weeks (p < 0.0005) and remission rates of 67% at week 1 and 94% at week 6. There was no evidence of EPSE and no worsening (and some improvement) of cognition. CONCLUSION: This suggests clinical benefits of quetiapine augmentation of SSRI/SNRI antidepressants with no worsening, and possible improvements in cognition.

Emerging treatments for major depression.

Antidepressant drugs were introduced into clinical practice in the mid-20th Century. While for the most part they have proven effective for the amelioration of depressive symptoms, they are associated with significant deficiencies. These well-recognized shortcomings have given impetus to the pursuit of new molecules that seek to improve on the efficacy, tolerability and safety of existing medications. The following article reviews several new compounds that may have antidepressant potential. Some are more advanced in development, having undergone clinical trials, whereas the clinical potential of others is yet to be explored. For this latter group of compounds, the antidepressant potential relies on their activity in validated animal models. Agomelatine and duloxetine are in the first category, having shown antidepressant efficacy in clinical trials. The blockade of cortisol secretion continues to be a focus of attention for the development of new antidepressants. Thus, synthesis inhibitors, nonpeptide antagonists of corticotropin-releasing factor and glucocorticoid receptor antagonists show some promise in clinical and preclinical tests. Antagonists of the neuropeptide substance P, vasopressin and neuropeptide Y represent a departure of approach from traditional monoamine receptor-based mechanisms. While the clinical results with one substance P antagonist have led to the cessation of further trials, other molecules are in development. Approaches to treatment based on glutamatergic transmission arose from observations in animal models. The clinical evaluation of such compounds awaits further development. The extent to which new agents can be judged to have met the goals of efficacy, tolerability and safety rely not only acute treatment trials but also on longer-term outcomes and postmarketing surveillance. Whether any of the new agents canvassed here prove to be significantly better than existing agents is clearly a judgement for the future.

Beyond the evidence: is there a place for antidepressant combinations in the pharmacotherapy of depression?

Up to 45% of patients with debilitating and potentially lethal depressive illness do not achieve remission with initial drug treatment. Using combinations of antidepressants as an early option for treatment-resistant depression has become increasingly common. Before trying combination therapy, it is essential first to ensure diagnosis is correct, and then to optimise antidepressant monotherapy, using an effective dose for an adequate period. Subsequently, augmentation of antidepressants with lithium and triiodothyronine should be considered, as these strategies are strongly supported by numerous clinical trials. Electroconvulsive therapy is the most effective treatment for severe depression. There is little evidence to support use of antidepressant combinations. Risk of toxicity and drug interactions mandate that combinations be used as a last resort, and only in specialist settings.

Selective effects of acute serotonin and catecholamine depletion on memory in healthy women.

There is converging evidence that brain serotonin and dopamine may selectively modulate learning and memory in humans. However, this has not been directly demonstrated. In the current study, we used the method of amino acid precursor depletion to explore the effects of low serotonin and catecholamine function on memory in healthy female volunteers. Participants completed three experimental sessions: (i) tryptophan depletion (TD to lower 5-HT); (ii) tyrosine and phenylalanine depletion (TPD to lower catecholamines); and (iii) a balanced control condition (Bal). All testing was conducted in a double-blind, placebo-controlled, crossover design. Cognitive and mood assessments were performed at baseline and 5 h after ingesting the amino acid mixture. Consistent with previous studies, TD impaired declarative memory consolidation on a structured word-learning task, while TPD, acting to lower brain dopamine availability, impaired spatial working memory. No secondary deficits were observed on measures of attention, short-term memory or subjective mood state. These findings suggest that low brain serotonin versus dopamine selectively impairs memory performance in humans. This may shed light on the role of these neurotransmitters in disorders that are characterized by significant memory impairment.

The treatment of depression with different formulations of venlafaxine: a comparative analysis.

Venlafaxine is the first of a group of antidepressants that show dual reuptake inhibition of serotonin and noradrenaline (SNRIs). Originally marketed in an immediate release (IR) formulation a microencapsulated, extended release (XR) formulation is now available. Significant differences exist between these two formulations with respect to pharmacokinetic parameters which have an impact on clinical use. The XR has lower maximum plasma concentrations (Cmax) and achieves these at a later time (higher Tmax). The longer apparent elimination half-life of the drug after single XR doses suggests that it is suitable for once daily dosing compared with the twice daily dosing regimen required by the IR formulation. With respect to antidepressant efficacy the XR formulation is equivalent to other marketed antidepressants and to the IR formulation. Consistent with its pharmacokinetic properties the use of the XR formulation is associated with less nausea and dizziness at the initiation of therapy. While in clinical usage XR might be expected to increase compliance with medication and to reduce discontinuation syndromes there are few comparative studies for which this has been evaluated. The XR formulation of venlafaxine is no worse than the IR form with respect to tolerability and offers some benefits to patients in terms of ease of use. On the other hand there does not appear to be any increase in the efficacy of the active agent.

Dual action antidepressants and some important considerations.

OBJECTIVE: To review controlled studies of long-term treatment and their side-effects with newer dual action antidepressants following an acute episode of major depression. METHOD: A literature review (MedLine) was undertaken and references were selected for their relevance and methodology in describing their contribution to the examination of our objective. RESULT AND CONCLUSION: Three dual action antidepressants are identified: venlafaxine, mirtazapine and milnacipran. These are more effective and better tolerated than the older tricyclic antidepressants in the treatment of an acute episode of depression and in the prevention of relapse. They also offer advantages in that they lack autonomic side-effects of the tricyclics. However, sedation, nausea and sexual side-effects may occur with venlafaxine, and weight gain with mirtazapine.

Olanzapine excretion in human breast milk: estimation of infant exposure.

Newer antipsychotic drugs offer significant clinical advantages for the treatment of psychosis. In particular for the treatment of postpartum disorders newer agents may be suited due to their favourable side-effect profiles. Of concern is the passage of the drugs into breast milk and what potential risks this poses for an infant who is breastfed. The excretion of olanzapine into the breast milk of five lactating women with postpartum psychosis was examined in this study. Nine pairs of plasma and breast-milk samples were collected and the concentration of olanzapine determined by high-performance liquid chromatography. Single-point milk-to-plasma ratios were calculated and ranged from 0.2 to 0.84 with a mean of 0.46. The median relative infant dose was 1.6% (range 0-2.5%) of the weight-adjusted maternal dose. During the study period, there were no apparent ill effects on the infant as a consequence of exposure to these doses of olanzapine. As with other antipsychotic drugs this study demonstrates that olanzapine passes into breast milk. The long-term effects of exposure in infants exposed to olanzapine requires further investigation.

In vitro metabolism of mirtazapine enantiomers by human cytochrome P450 enzymes.

The metabolism of mirtazapine enantiomers was investigated in vitro using human lymphoblast microsomes transfected with human cDNA to overexpress either CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and assayed for mirtazapine enantiomers using a validated chiral method of high-performance liquid chromatography. (+)-Mirtazapine was extensively metabolised by CYP2D6 (K(m) = 9.3 +/- 3.3 &mgr;mol/l, V(max) = 40.9 +/- 7.9 &mgr;mol/h/mg, intrinsic clearance = 4.41 l/h/mg). CYP1A2 and CYP3A4 showed low metabolic activity towards (+)-mirtazapine and (-)-mirtazapine respectively. Neither CYP2C9 nor CYP2C19 appeared to be involved in the metabolism of the enantiomers of mirtazapine. Copyright 2001 John Wiley & Sons, Ltd.

Sertraline in paired blood plasma and breast-milk samples from nursing mothers.

Paired blood and breast-milk samples were collected from 10 nursing mothers receiving sertraline. Samples were collected at steady state when the patients had been taking stable doses of 50-150 mg/day over several weeks. Sertraline concentrations in both fluids were determined using a specific, validated HPLC method. Plasma and milk concentrations showed a wide inter-individual variability for the same dose. Mean plasma concentrations were linearly related to dose, but this was not the case for breast-milk concentrations. An overall milk to plasma ratio of 1.76+/-1.72 was recorded. The average dose to the infants ranged from 1.1 to 31.1 &mgr;g/kg, which is less than 2 per cent of the maternal dose per day. Further studies are necessary to determine if these doses are detrimental to the development of the infant. Copyright 2000 John Wiley & Sons, Ltd.

Subsensitive melatonin suppression by dim white light: possible biological marker of panic disorder.

Light is involved in providing entrainment of circadian rhythms and the suppression of the pineal hormone melatonin. In patients with affective disorders, there have been indications of circadian as well as seasonal variation in illness, which may be reflected in melatonin production. Varying sensitivity to light has been noted within healthy individuals as well as in some patients with affective disorders. Recent evidence suggests that patients with panic disorder may have an altered and phase-delayed melatonin rhythm. The present study examined the nocturnal plasma melatonin rhythm in patients with panic disorder, and also examined their melatonin sensitivity to dim light. The melatonin rhythm was examined in 6 patients with panic disorder and 8 controls. The melatonin sensitivity to dim white light (200 lx) was examined in 8 patients with panic disorder and 63 controls and was compared to that of a group of 7 patients with other anxiety disorders. Patients with panic disorder demonstrated a trend towards higher and delayed peak melatonin levels compared to controls. Patients with panic disorder also had a subsensitive melatonin suppression by dim white light, compared to controls and patients with other anxiety disorders (p<0.005). The phase-delayed circadian rhythm observed in patients with panic disorder may be secondary to the subsensitivity of the melatonin response to light. It is hypothesized that the subsensitivity may be due to abnormal neurotransmitter/receptor systems involved in regulation of melatonin suppression and circadian rhythmicity, and may lead to phase- delayed circadian rhythms. The melatonin subsensitivity to light may be used as a biological marker of panic disorder.