http://dosequis.colorado.edu/Courses/BrainWeb/papers/BP2.pdf

Pathways underlying neuroprogression in bipolar disorder : focus on inflammation, oxidative stress and neurotrophic factors

Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression.

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

/pdf/statin-adverse-effects-a-review-of-the-literature-and-5byfkzyay5.pdf

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

https://researchrepository.murdoch.edu.au/13504/1/A_review_of_lifestyle_factors_that_contribute_to_important_pathways_associated_with_major_depression%2Dfinal_manuscript1.pdf

A review of lifestyle factors that contribute to important pathways associated with major depression: Diet, sleep and exercise

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

/pdf/differential-responses-to-lithium-in-hyperexcitable-neurons-46fizcj1je.pdf

Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

Introduction:Mitochondria are intracellular organelles involved in adenosine triphosphate production. The literature has established the presence of mitochondrial dysfunction in some subjects with psychiatric disorders. Also, there are multiple reports of patients with mitochondrial dysfunction who have various psychiatric disorders. Although the literature on mitochondrial dysfunction and its relation to psychiatric disorders is growing, there remain many unanswered questions.Objective:To review subjects with mitochondrial cytopathies for prevalence of psychiatric comorbidity.Methods:For this study, 36 adults were interviewed. The Mini International Neuropsychiatric Interview and the Short-Form 36 Health Survey, version 1 were used.Results:Lifetime diagnoses included 54% major depressive disorder, 17% bipolar disorder, and 11% panic disorder. These prevalence rates are compared with the general population and subjects with cancer and epilepsy. Subjects with a comorbid psychiatric diagnosis were older (P=.05), had more hospital admissions (P=.02), more medical conditions (P=.01), and lower quality of life (P=.01) than subjects with mitochondrial disease alone.Conclusion:Clinicians caring for persons with mitochondrial cytopathies should note the high prevalence of psychiatric problems. Also, this comorbidity might have etiological and therapeutic implications.

Psychiatric comorbidity in 36 adults with mitochondrial cytopathies.

Baking-soda pica in an adolescent patient

Recent observations reveal a correlation between group A-beta-hemolytic streptococcal infection (GABHS), and the onset of obsessive-compulsive disorder (OCD) and tics in some individuals. A 1998 study examined 50 cases of this disorder known as Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS) and identified 5 diagnostic criteria based on observation of affected individuals. The criteria are (1) presence of OCD and/or tic disorder, (2) prepubertal onset, (3) abrupt symptom onset, (4) neuropsychiatric abnormalities, and (5) temporal association between symptom exacerbation and GABHS infection.1 The most problematic aspect of these criteria is the high background carrier frequency of GABHS, reported to be as high as 20% in the general population. It is hypothesized that some strains of GABHS bacteria provoke production of antibodies that attack the basal ganglia, resulting in disrupted neuronal function.2,3 Although unclear why this response occurs in only some individuals, it is likely that genetic susceptibility plays a role. Many PANDAS patients have a family history of psychiatric disorders and monoclonal antibody D8/17, a genetic marker with increased expression in PANDAS patients,4,5 which is also more frequent in patients with Tourette syndrome who do not meet criteria for PANDAS. For years, the treatment of choice for OCD has been selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy.6 Some PANDAS patients, however, respond better to immunosuppressive therapies such as therapeutic plasma exchange (TPE) and intravenous immunoglobin(IVIG).7,8 Research is currently underway to determine the risks and benefits of these treatment options and to determine the effectiveness of prophylactic antibiotic treatment that will hopefully prevent recurrent symptom exacerbation.9,10 Currently, there are differences in diagnostic evaluations, management, or treatment of PANDAS patients. The purpose of this case series is to alert physicians to particular risk factors, to suggest key elements to include in evaluation of possible PANDAS patients, and to describe potential treatments.

Varied Presentation of Pandas: A Case Series

https://www.childpsych.theclinics.com/article/S1056-4993(02)00028-7/pdf

Kathleen Quinn

Papers

Psychiatric comorbidity in 36 adults with mitochondrial cytopathies.

Baking-soda pica in an adolescent patient

Varied Presentation of Pandas: A Case Series

Juveniles on trial.

Ethical Dilemmas in Forensic Child and Adolescent Psychiatry