Neural circuits mediating stress.

Stress has been linked to the pathophysiology and pathogenesis of mood and anxiety disorders. Over the past few years, our understanding of the brain and neuroendocrine circuits that are linked to the stress response have increased dramatically. This article reviews a series of animal and human studies aimed at understanding what are the pathways by which stress is perceived, processed, and transduced into a neuroendocrine response. We focus on the classic stress circuit: the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. These studies indicate that the LHPA stress circuit is a complex system with multiple control mechanisms and that these mechanisms are altered in pathological states, such as chronic stress and depression. These studies also suggest that the interactions between the LHPA and other neurotransmitters, such as serotonin, may provide the neurobiological substrate by which stress may affect mood.     

The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders

Treatment options to relieve the diverse symptoms encountered in patients with bipolar disorders include not only mood stabilizers, but also anxiolytics, new anticonvulsants, antidepressants, and antipsychotics. These agents have widely varying mechanisms of action, which could contribute to the heterogeneity of clinical effects seen in practice. Several of these medications, especially those with anticonvulsant effects, enhance gamma-aminobutyric acid (GABA) inhibitory neurotransmission and/or attenuate glutamate excitatory neurotransmission. We review the efficacy and tolerability of these diverse treatment options in bipolar disorders and explore possible relationships between clinical effects and GABAergic and antiglutamatergic mechanisms of action.     

Sex differences in anxiety and depression: Role of testosterone

Compelling evidence exists for pervasive sex differences in pathological conditions, including anxiety and depressive disorders, with females more than twice as likely to be afflicted. Gonadal hormones may be a major factor in this disparity, given that women are more likely to experience mood disturbances during times of hormonal flux, and testosterone may have protective benefits against anxiety and depression. In this review we focus on the effects of testosterone in males and females, revealed in both human and animal studies. We also present possible neurobiological mechanisms underlying testosterone’s mostly protective benefits, including the brain regions, neural circuits, and cellular and molecular pathways involved. While the precise underlying mechanisms remain unclear, both activational and organizational effects of testosterone appear to contribute to these effects. Future clinical studies are necessary in order to better understand when and how testosterone therapy may be effective in both sexes.     

Cellular plasticity and resilience and the pathophysiology of severe mood disorders

Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood disorders.     

Structural and synaptic plasticity in stress-related disorders

Abstract Stress can have a lasting impact on the structure and function of brain circuitry that results in long-lasting changes in the behavior of an organism. Synaptic plasticity is the mechanism by which information is stored and maintained within individual synapses, neurons, and neuronal circuits to guide the behavior of an organism. Although these mechanisms allow the organism to adapt to its constantly evolving environment, not all of these adaptations are beneficial. Under prolonged bouts of physical or psychological stress, these mechanisms become dysregulated, and the connectivity between brain regions becomes unbalanced, resulting in pathological behaviors. In this review, we highlight the effects of stress on the structure and function of neurons within the mesocorticolimbic brain systems known to regulate mood and motivation. We then discuss the implications of these spine adaptations on neuronal activity and pathological behaviors implicated in mood disorders. Finally, we end by discussing recent brain imaging studies in human depression within the context of these basic findings to provide insight into the underlying mechanisms leading to neural dysfunction in depression.     

Anti-tumor necrosis factor-α therapy is associated with less frequent mood and anxiety disorders in patients with rheumatoid arthritis

Aims:  The purpose of the present study was to examine the current prevalence of mood and anxiety disorders, and factors related to mood and anxiety disorders in patients with rheumatoid arthritis (RA).
Method:  The study sample included 83 consecutive patients with RA who were admitted to a rheumatology outpatient clinic. Diagnoses of psychiatric disorders were determined using the Structured Clinical Interview for DSM-IV (SCID-I). To assess physical disability and disease activity, the Health Assessment Questionnaire and the Disease Activity Score, respectively, were used.
Results:  The prevalence of any mood or any anxiety disorder was 43.4%. The two most common psychiatric diagnoses were major depression (21.7%) and generalized anxiety disorder (16.9%). Mood and anxiety disorders were unrelated to sociodemographic features, disease-related factors, and medications for RA except anti-tumor necrosis factor-α (TNF-α). These disorders, however, were identified less frequently in patients with RA receiving anti-TNF-α drugs compared to patients who did not receive such medications.
Conclusion:  Patients with RA frequently have mood and anxiety disorders, and anti-TNF-α drugs may be useful for the mental status of these patients.     

Théorie multidimensionnelle et computationnelle de l’humeur

What is mood? Despite its crucial place in psychiatric nosography and cognitive science, it is still difficult to delimit its conceptual ground. The distinction between emotion and mood is ambiguous: mood is often presented as an affective state that is more prolonged and less intense than emotion, or as an affective polarity distinguishing high and low mood swinging around a baseline. However, these definitions do not match the clinical reality of mood disorders such as unipolar depression and bipolar disorder, and do not allow us to understand the effect of mood on behaviour, perception and cognition. In this paper, we propose a multidimensional and computational theory of mood inspired by contemporary hypotheses in theoretical neuroscience and philosophy of emotion. After suggesting an operational distinction between emotion and mood, we show how a succession of emotions can cumulatively generate congruent mood over time, making mood an emerging state from emotion. We then present how mood determines mental and behavioral states when interacting with the environment, constituting a dispositional state of emotion, perception, belief, and action. Using this theoretical framework, we propose a computational representation of the emerging and dispositional dimensions of mood by formalizing mood as a layer of third-order Bayesian beliefs encoding the precision of emotion, and regulated by prediction errors associated with interoceptive predictions. Finally, we show how this theoretical framework sheds light on the processes involved in mood disorders, the emergence of mood congruent beliefs, or the mechanisms of antidepressant treatments in clinical psychiatry.     

Cognitive and neurological impairment in mood disorders.

Disorders of mood are accompanied by a range of cognitive and neurological impairments. Similar types of cognitive deficits are shared by patients with unipolar depression and bipolar disorder. Given the disparate clinical nature of these two disorders, it is interesting and informative to understand that they share common impairments in cognition. Neuro-imaging studies indicate that these impairments in both patient populations may be subserved by disruptions of the dorsal lateral and ventral medial PFC. An important problem that remains for clinicians is that some neurological symptoms are linked specifically to the adverse pharmacological effects of antidepressant agents, mood stabilizers, and neuroleptic agents.Research has shown a relation between mood and cognitive ability.Studies also have shown an association between mood and specific types of neurological dysfunction. Although few studies have examined all three symptom domains within one investigation, preliminary reports indicate that mood, cognition, and motor function may be linked to one another by complex mechanisms. Moreover, either type of abnormality that persists in the euthymic state suggests that a fundamental neural dysfunction is unaffected by treatment with existing means. Understanding the neural mechanisms that underlie mood, cognition, and movements may help to devise better treatments that do not influence cognitive or neurological functions,yet treat mood successfully.     

Translating depression biomarkers for improved targeted therapies

Mood disorders are among the most common medical conditions and cause amongst the greatest disease burden. Currently approved antidepressants target monoamine pathways; these medicines take many weeks to relieve symptoms, and most patients do not have sustained responses. This review will highlight recent advances in translational science identifying dysfunctional biochemical processes and neuronal circuits associated with mood disorders. We will also summarize strategies for targeting these pathways and for enhancing synaptic plasticity to develop most effective and rapidly acting antidepressant therapies.