Mitochondrial DNA oxidation, methylation, and copy number alterations in major and bipolar depression.

Background: Mood disorders are common disabling psychiatric disorders caused by both genetic and environmental factors. Mitochondrial DNA (mtDNA) modifications and epigenetics are promising areas of research in depression since mitochondrial dysfunction has been associated with depression. In this study we aimed to investigate the mtDNA changes in depressive disorder (MDD) and bipolar disorder (BD). Methods: Displacement loop methylation (D-loop-met), relative mtDNA copy number (mtDNA-cn) and mtDNA oxidation (mtDNA-oxi) were investigated in DNA samples of individuals with MDD (n = 34), BD (n = 23), and healthy controls (HC; n = 40) using the Real-Time Polymerase Chain Reaction (RT-PCR). Blood samples were obtained from a subset of individuals with MDD (n = 15) during a depressive episode (baseline) and after remission (8th week). Results: The study groups exhibited significant differences in D-loop-met (p = 0.020), while relative mtDNA-cn and mtDNA-oxi showed comparable results. During the remission phase (8th week), there were lower levels of relative mtDNA-cn (Z = -2.783, p = 0.005) and D-loop-met (Z = -3.180, p = 0.001) compared to the acute MDD baseline, with no significant change in mtDNA-oxi levels (Z = -1.193, p = 0.233). Conclusion: Our findings indicate significantly increased D-loop methylation in MDD compared to BD and HCs, suggesting distinct mtDNA modifications in these conditions. Moreover, the observed alterations in relative mtDNA-cn and D-loop-met during remission suggest a potential role of mtDNA alterations in the pathophysiology of MDD. Future studies may provide valuable insights into the dynamics of mtDNA modifications in both disorders and their response to treatment.

Clinical risk factors, phenomenology and the impact of clozapine induced obsessive compulsive symptoms.

The aim of this study was to investigate the clinical risk factors, phenomenology and the impact of clozapine induced obsessive-compulsive symptoms (OCS) in patients with schizophrenia. One hundred twenty-two patients receiving clozapine treatment for at least 6 weeks were assessed with Structured Clinical Interview for Axis-I Disorders for DSM-IV, Positive and Negative Syndrome Scale, Yale-Brown Obsessive Compulsive Scale and Checklist, Calgary Depression Scale, Clinical Global Impression Scale and WHO-Disability Assessment Schedule-II. Information about past and current clinical status were gathered through clinical interviews and medical records. With clozapine 44.3% of the patients had de novo OCS, 33.6% had OCS both before and after clozapine, 21.3% didn't report any OCS. Clozapine doses, clozapine and norclozapine plasma levels were not significantly different. Severity of OCS was affected by clozapine and norclozapine plasma levels, and correlated with increased disability. Obsessions were less in clozapine induced OCS group, and compulsions, especially of checking subtypes, were predominant, compared to the group with prior history of OCS, who reported a significant increase in checking compulsion after clozapine treatment. Clozapine induced OCS should be considered during cost/benefit assessment of clozapine treatment, and understanding the risk factors and its different phenomenology may shed light into the underlying mechanisms.

Reasons for clozapine discontinuation in patients with treatment-resistant schizophrenia.

Although clozapine is more effective than other antipsychotics in the treatment of schizophrenia, the rate of its discontinuation is also high. The aim of this retrospective chart-review study was to investigate the causes of clozapine discontinuation in patients with treatment-resistant schizophrenia. This study included a total of 396 patients with schizophrenia, 240 still on clozapine therapy and 156 who discontinued clozapine, and compared their clinical characteristics. Those who discontinued clozapine had a longer history of illness and more hospitalizations before clozapine and tended to be older. Inadequate response was more common among clozapine discontinuers compared to continuers. The most common reason for discontinuation was the side-effects associated with clozapine (49%). Discontinuation from patient decision or by the psychiatrist due to noncompliance was the second (29.7%) and discontinuation due to lack of efficacy was the third most frequent reason (21.3%). The patients who discontinued clozapine because of cardiac side effects were younger, had shorter duration of clozapine use, and had lower maximum clozapine dose compared to the other discontinuers. Our findings point out the importance of enhancing psychiatrists' ability to handle manageable side effects to minimize discontinuations and maximize the benefits of clozapine in patients with treatment-resistant schizophrenia.