Possible pharmacogenetic factors in clozapine treatment failure: a case report.

There is still much to learn about the predictors of therapeutic response in psychiatry, but progress is gradually being made and precision psychiatry is an exciting and emerging subspeciality in this field. This is critically important in the treatment of refractory psychotic disorders, where clozapine is the only evidence-based treatment but only about half the patients experience an adequate response. In this case report, we explore the possible biological mechanisms underlying treatment failure and discuss possible ways of improving clinical outcomes. Further work is required to fully understand why some patients fail to respond to the most effective treatment in refractory schizophrenia. Therapeutic drug monitoring together with early pharmacogenetic testing may offer a path for some patients with refractory psychotic symptoms unresponsive to clozapine treatment.

Differential effect of interferon-alpha treatment on AEA and 2-AG levels.

The endocannabinoid (eCB) system is one of the key players in immunoregulation, and reduced activity of the eCB system has been linked with depressive-like behaviours in animal studies and depression in clinical samples. There is a well-established link between immune activation and depression, such as following the administration of the pro-inflammatory cytokine, interferon-α (IFN-α), used to treat hepatitis C viral (HCV) infection. However, the role of peripheral endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), following immunotherapy with IFN-α and in IFN-α -induced depression, have not been examined yet. In this study, we investigated whether circulating AEA and 2-AG were modified by treatment with IFN-α and whether they were involved in the development of IFN-α-induced depression. We also explored whether circulating eCBs were associated with peripheral cytokines during and after IFN-α treatment. We measured serum concentrations of AEA and 2-AG using High Performance Liquid Chromatography with Tandem Mass Spectrometry, and serum concentrations of cytokines using Meso Scale Discovery electrochemiluminescence V-PLEX assay, in 70 patients with HCV infection and 41 healthy subjects. We assessed HCV patients at baseline, IFN-α-treatment weeks (TW) 4 and 24, end of treatment (END) and at six months follow-up (FU). We assessed depression using M.I.N.I. International Neuropsychiatric Interview. We found a different pattern of change in peripheral AEA and 2-AG during and after IFN-α treatment. Whilst 2-AG increased earlier in immunotherapy (TW4), remained elevated throughout treatment, and reduced at six months follow-up (FU), AEA increased later in treatment (TW24) and remained elevated six months post-treatment. We also found that baseline levels of AEA were lower in HCV patients compared with healthy controls, whereas there were no differences in 2-AG levels. Interestingly, AEA, but not 2-AG, was significantly, negatively correlated with interleukin (IL)-2 and IL-17a at six months follow-up. We did not find any difference in both eCBs between patients with and without IFN-α-induced depression, at any time point. Our findings suggest that AEA and 2-AG are involved in different stages of immunoregulation following IFN-α treatment, where AEA might be involved in chronic inflammation. Lack of association between peripheral eCBs and IFN-α-induced depression suggests that different biological mechanisms may underpin inflammation-induced depression compared with classic "psychiatric" depression, or that any changes in the eCB system in depression may not be captured by peripheral AEA and 2-AG.

Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues.

There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined. Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM. Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems' abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.

A brain centred view of psychiatric comorbidity in tinnitus: from otology to hodology.

Introduction. Comorbid psychiatric disorders are frequent among patients affected by tinnitus. There are mutual clinical influences between tinnitus and psychiatric disorders, as well as neurobiological relations based on partially overlapping hodological and neuroplastic phenomena. The aim of the present paper is to review the evidence of alterations in brain networks underlying tinnitus physiopathology and to discuss them in light of the current knowledge of the neurobiology of psychiatric disorders. Methods. Relevant literature was identified through a search on Medline and PubMed; search terms included tinnitus, brain, plasticity, cortex, network, and pathways. Results. Tinnitus phenomenon results from systemic-neurootological triggers followed by neuronal remapping within several auditory and nonauditory pathways. Plastic reorganization and white matter alterations within limbic system, arcuate fasciculus, insula, salience network, dorsolateral prefrontal cortex, auditory pathways, ffrontocortical, and thalamocortical networks are discussed. Discussion. Several overlapping brain network alterations do exist between tinnitus and psychiatric disorders. Tinnitus, initially related to a clinicoanatomical approach based on a cortical localizationism, could be better explained by an holistic or associationist approach considering psychic functions and tinnitus as emergent properties of partially overlapping large-scale neural networks.

Tinnitus: clinical experience of the psychosomatic connection.

BACKGROUND: The connection between psychopathology and tinnitus is complex and not adequately studied. The aim of this study is to investigate the relationship between tinnitus and psychiatric comorbidities from different points of view: categorical, dimensional, temperamental, and perceived stress level. METHODS: Two hundred and thirty-nine patients affected by tinnitus were recruited between January and October 2012. Patients underwent a preliminary battery of tests including the Tinnitus Handicap Inventory (THI), Symptom Check List (SCL90-R), Temperament and Character Inventory (TCI), and Stress-Related Vulnerability Scale (VRS), and eventually a full psychiatric evaluation. RESULTS: One hundred and fourteen patients (48% of the total sample) presented psychiatric comorbidity. Among these, a higher prevalence of depression, somatization, obsession, and anxiety was found. More than 41% of patients affected by decompensated tinnitus reported a family history of psychiatric disorders. Significant positive correlations between the psychopathological screening tools (SCL90-R and VRS) and THI were found. Patients affected by comorbid psychiatric disorder showed specific temperamental and characterial predispositions. CONCLUSION: Psychiatric comorbidity in subjects affected by tinnitus is frequent. Stress can be considered as a factor leading to damage and dysfunction of the auditory apparatus. The vulnerability to neurotic disorders and the lack of coping capabilities can play a critical role in the clinical history of patients affected by severe tinnitus.