[11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging
ABSTRACT RationaleLack of benefit from antidepressant drug therapy is a major source of human suffering, affecting at least 25% of people with
major depressive disorder. We want to know whether nonresponse to antidepressants can be linked to aberrant neuroreceptor
ObjectiveThis study aims to assess the antidepressant binding in brain regions of depressed nonresponders compared with healthy controls.
Materials and methodsHealthy volunteers and depressed subjects who had failed to benefit from at least 2 antidepressant treatments were recruited
by newspaper advertisements. All subjects had received no antidepressant medication for at least 2months before positron
emission tomography (PET) that was carried out with [11C]mirtazapine. Kinetic parameters of [11C]mirtazapine were determined from PET data in selected brain regions by the simplified reference tissue model.
ResultsBinding potentials of [11C]mirtazapine in cerebral cortical regions were lower in depressed nonresponders than in healthy controls. Removal rates of
[11C]mirtazapine were higher in diencephalic regions of depressed nonresponders than in healthy controls.
ConclusionsPET neuroimaging with [11C]mirtazapine showed aberrant neuroreceptor binding in brain regions of depressed subjects who had failed to benefit from
treatment with antidepressant drugs.
- SourceAvailable from: Marcelo Berlim[show abstract] [hide abstract]
ABSTRACT: To summarize and discuss the conceptual and operational definitions of treatment resistant/refractory depression (TRD) by systematically reviewing randomized controlled trials (RCTs) on its somatic treatment. We searched the MEDLINE, Cochrane Library, PsycINFO, and EMBASE for potentially relevant RCTs on the somatic treatment of TRD published from January 1996 to June 2006. Studies were included if they: (a) enrolled patients at least 18 years old with a primary diagnosis of unipolar major depression considered resistant/refractory to treatment at baseline, (b) had a randomized design, (c) were published in peer-reviewed journals, and (d) were written in English. Trials that enrolled patients with secondary depression were excluded from our review. Finally, the bibliographies of relevant articles were hand-searched for additional references. In total, 233 full electronic references were retrieved, from which 47 meet the inclusion criteria. Through a standardized form, we collected data describing the diagnostic procedure, the terminology and definition of TRD employed, the methodology for assessing the adequacy of previous treatments (in terms of type of ascertainment, dose, and duration), and the minimum required depressive symptoms at baseline. Overall, RCTs diverged regarding the majority of the conceptual and methodological issues involved in the ascertainment of TRD. For example, eleven terms were used to describe resistance/refractoriness in depression, and six different criteria were employed to define the categorical presence of TRD (ranging form non-response to one antidepressant to non-response to two or more antidepressants from different pharmacological classes). Regarding the evaluation of previous treatments, the majority of RCTs did not use systematic methods to gather data, and diverge substantially on the minimum acceptable medication doses and trial durations. There is a clear need for an internationally shared framework of concepts and methods for the investigation of TRD that could reduce current idiosyncrasies and provide a reference system. Such a foundation is essential for the interpretation of research findings and for their translation to clinical practice.European Neuropsychopharmacology 12/2007; 17(11):696-707. · 4.60 Impact Factor
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ABSTRACT: Definitive conclusions on the role of serotonin receptors and transporter in suicide and depression have been elusive in studies of postmortem brain tissue. A number of methodological differences in these studies have made it difficult to reach a consensus, but crucial issues are being identified and incorporated into newer studies. This review will follow the evolution of serotonin receptor and transporter studies in postmortem tissues that initially focused on suicide and gradually incorporated depressive disorders as psychiatric assessments were increasingly performed. Studies in postmortem tissues on the serotonin-1A and serotonin-2A receptors and the serotonin transporter will be reviewed and compared with imaging studies of the same sites in depressed subjects. Critical issues to control in future studies of serotonin receptors in postmortem tissues include variables such as the cause of death (i.e. suicide), the specific psychiatric diagnoses of the subjects, whether the disorder was in remission at the time of death, long-term medication histories, psychoactive substance use disorders, the smoking history, the hemisphere from which tissues were dissected, and the specific cytoarchitectonic region to be evaluated. Carefully controlled studies in postmortem tissues will ensure a greater likelihood of reaching a consensus on the involvement of monoamine measures in the etiology of depression.Journal of Psychiatric Research 01/2003; 37(5):357-73. · 4.07 Impact Factor
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ABSTRACT: The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.CNS spectrums 09/2008; 13(8):663-81. · 1.73 Impact Factor