Роль воспалительных процессов в формировании резистентности к лечению депрессии

Inflammation may also be relevant to depression prevention and relapse. There are multiple clinical factors associated with both inflammation and TRD that can be addressed through lifestyle changes. Treating obesity with diet and exercise in patients with increased inflammation is a primary example. In a recent clinical trial of partial treatment responders, depressed patients with increased TNF levels were more likely to respond to an add-on exercise intervention than were patients who were partially responsive to an SSRI. Another consideration is behavioral stress management including compassion meditation training, which has been shown to reduce inflammatory responses to a laboratory psychosocial stressor.

Exercise and meditation have been associated with an increased parasympathetic tone, which, in turn, has been associated with decreased inflammatory tone. These effects are likely related to parasympathetic activation of T cells that produce acetylcholine that binds to the α subunit of the nicotinic acetylcholine receptor, leading to inhibition of NF-κB.41 Finally, optimizing the management of medical illnesses associated with inflammation may also reduce depression symptoms and improve treatment response.

Inflammation and Treatment Resistance in Major Depression: The Perfect Storm

Допаминовая система больных шизофренией резистентных к лечению

The authors conclude: 'Our findings suggest that there may be a different molecular mechanism leading to schizophrenia in patients who do not respond to anti-psychotic medication. Identifying the precise molecular pathway particularly in these patients is of utmost importance and will help inform the development of much-needed novel treatments.'
Researchers used PET scan imaging to investigate dopamine synthesis capacity in 12 patients with schizophrenia who did not respond to treatment, 12 who did, and 12 healthy controls. They found that schizophrenia patients whose illness was resistant to antipsychotic treatment have relatively normal levels of dopamine synthesis capacity which would explain why the dopamine blocking anti-psychotic medication was not effective in this group.

 Research may explain why some people with schizophrenia do not respond to treatment

Допамин и шизофрения

In this meta-analysis, Howes and colleagues studied the nature of dopaminergic dysfunction in schizophrenia. Data were gathered in vivo in 618 patients with schizophrenia and 606 controls using PET or single-photon emission CT. A highly significant elevation in presynaptic dopaminergic function was observed in patients with schizophrenia, with a large effect size but no alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability, but this was not evident in drug-naive patients and was influenced by the imaging approach used.

 The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment

In the current study, Demjaha and colleagues examined striatal dopamine synthesis capacity in 12 treatment-resistant and 12 treatment-responsive schizophrenia subjects, as well as in 12 healthy controls. They found that dopamine synthesis capacity was elevated in the treatment-responsive subjects, but not in the treatment-resistant subjects or in healthy controls. The elevation was most prominent in the associative and limbic striatal subdivisions.

 News Brief: Normal Dopamine Synthesis Capacity in Treatment-Resistant Schizophrenia

Механизм резистентности к лечению шизофрении

Scientists have discovered a molecular mechanism for resistance to antipsychotic medications, a finding that may pave the way for the development of new drugs to treat a significant proportion of schizophrenia patients who do not respond to these medications.

Investigators led by Javier González-Maeso, PhD, assistant professor of psychiatry and neurology, Mount Sinai School of Medicine in New York City, found that long-term administration of atypical antipsychotic drugs selectively upregulates expression of the enzyme histone deacetylase 2 (HDAC2) in both mouse and human frontal cortex.

This epigenetic change, which is dependent on serotonin 5-hydroxytryptamine 2A (5-HT2A) upregulation, leads to lower expression of the metabotropic glutamate 2 receptor (mGlu2), thereby limiting the therapeutic effects of atypical antipsychotic therapy, often leading to a recurrence of psychotic symptoms.

According to investigators, blocking this cascade of events with HDAC inhibitors may improve responses to atypical antipsychotic drug therapy.

"Together, these data suggest that HDAC2 may be a new therapeutic target to augment the treatment of schizophrenia.... Specifically, our findings encourage the development and testing of HDAC2-selective inhibitors for schizophrenia," the investigators write.

 New Discovery Raises Hope for Drug-Resistant Schizophrenia