Molecular analysis of brain tissue from alcoholics revealed numerous differences from normal controls, potentially providing a key link connecting the brain to behavior in chronic alcoholism. Also, another study connects autoimmunity to at least some cases of epilepsy, and a novel antipsychotic drug targets negative symptoms in schizophrenia.
This Is Your Brain on Alcohol for Years
Brain autopsies in 20 alcoholic individuals versus 20 matched controls revealed a spectrum of differences in protein types and concentrations that may “provide a molecular basis for some of the neuronal and behavioral abnormalities attributed to alcoholics,” according to a British-Spanish research group.
Led by Amaia Erdozain, PhD, and Wayne Carter, PhD, of the University of Nottingham in England, the researchers examined the prefrontal cortex (Brodmann area 9) in exquisite detail, using gel electrophoresis, two types of mass spectrometry, and other assays to identify and quantify proteins present in the postmortem tissue.
Key findings in the alcoholic specimens compared with controls included:
- Thinner cytoskeletons around cell nuclei in cortical and subcortical neurons
- Disrupted subcortical neuron patterning
- “Dramatic” reductions in spectrin-beta II and in alpha- and beta-tubulins
- Greater alpha-tubulin acetylation
- Reduced proteasome activity
Not only might these molecular changes reflect or cause the clinical effects of chronic alcoholism, they may also contribute to the overall brain atrophy seen in the condition, the researchers suggested in their report, appearing online in PLoS ONE.
Limitations to the study included less-than-perfect assays for some proteins and variations among the alcoholic subjects in age, duration of alcoholism, and cumulative alcohol intake; these subjects may not be representative of alcoholics in the general population.
Autoimmune Basis for Epilepsy
Another study supports the notion that at least some cases of epilepsy have their roots in autoimmunity, and this one comes at the question from a new angle.
Analysis of U.S. insurance claims data on some 2.5 million people found that a diagnosis of epilepsy was nearly four-fold more common among those with autoimmune disorders, according to a report in JAMA Neurology.
Kenneth D. Mandl, MD, MPH, of Harvard Medical School in Boston, and colleagues, compared the presence of an epilepsy diagnosis in insurance plan members who had any of 12 autoimmune disorders listed in their records — such as psoriasis, rheumatoid arthritis, or celiac disease — versus other plan members
After adjusting for other factors, they found an odds ratio of 3.8 for an epilepsy diagnosis (95% CI 3.6-4.0) associated with any of these conditions. No one type of autoimmunity stood out as a special risk factor, the authors indicated.
But children in the sample appeared to be more susceptible than adults to epilepsy in conjunction with autoimmunity, with an odds ratio of 5.2 (95% CI 4.1-6.5).
Other studies have also suggested that epilepsy may have an autoimmune component, especially in cases that don’t respond to conventional anti-seizure medications.
For example, Italian researchers reported last year that they had found neural autoantigens in 14 of 72 patients with drug-resistant epilepsy.
And Mayo Clinic researchers said last fall that immunotherapies such as intravenous immunoglobulin or steroids may be tried in patients with treatment-refractory epilepsy, after achieving success in 18 out of 29 patients.
Mandl and colleagues noted that their study was based on claims data, which may be flawed and/or incomplete. Nevertheless, they wrote, “The potential role of autoimmunity must be given due consideration in epilepsy so that we are not overlooking a treatable cause.”
Novel Antipsychotic Targets Negative Symptoms
An investigational drug called bitopertin showed promise for addressing the negative symptoms of schizophrenia in a phase II trial, researchers reported, although they haven’t been matched in later studies.
In an 8-week, 323-patient trial, those receiving the oral drug according to the study protocol showed significantly greater reductions in negative symptoms than the placebo group, according to Luca Santarelli, MD, of F. Hoffmann-La Roche in Basel, Switzerland, and colleagues writing online in JAMA Psychiatry.
Roche is developing the drug and funded the trial.
Other antipsychotic drugs have proven effective in treating hallucinations and other types of disturbed thinking that define schizophrenia. But negative symptoms — such as apathy and social withdrawal — have been a tougher nut to crack with pharmacotherapies. Old-line antipsychotics such as chlorpromazine did little to improve the negative symptoms; newer “atypical” agents were billed as doing a better job, but have still fallen far short of optimal.
As Santarelli and colleagues explained in their journal report, this lack of effect on negative symptoms “may explain why as few as 30% of patients treated with second-generation antipsychotics achieve functional or symptomatic remission and even fewer attain full recovery.”
Bitopertin has a novel mechanism of action. It inhibits the reuptake of glycine, which is intended to boost activity of so-called NMDA receptors. Impaired NMDA activity is believed to be at the root of schizophrenia’s negative symptoms as well as a contributor to the positive symptoms.
In Roche’s phase II study, patients were randomized in groups of about 80 to three doses of bitopertin (10, 30, or 60 mg/day orally) or placebo.
Inclusion criteria were designed to enroll patients whose symptoms were predominantly on the negative side. Hence, patients with scores of more than 28 on the eight positive symptoms evaluated in the Positive and Negative Syndrome Scale (PANSS) were excluded, as were those with especially high scores on certain positive symptoms. Patients were allowed to remain on conventional antipsychotics that they were taking at recruitment, except for clozapine.
For the primary outcome in a per-protocol analysis that excluded 92 participants, change from baseline in PANSS negative symptom scores, results were as follows:
- 10 mg/day: -6.50 (95% CI minus 7.66-minus 5.34)
- 30 mg/day: -6.65 (95% CI minus 7.84-minus 5.46)
- 60 mg/day: -5.21 (95% CI minus 6.44-minus 3.98)
- Placebo: -4.86 (95% CI minus 6.01-minus 3.71)
The declines were significantly larger for the 10- and 30-mg/day group than in the placebo group (both P<0.05) but not for the 60-mg/day group (P=0.68).
A responder analysis showed a similar pattern. Using a 20% decrease in total PANSS negative symptom score as the threshold for response, this was achieved by 65% and 60% of the 10- and 30-mg/day group compared with 43% for both the placebo and 60-mg/day groups. For only the lowest dosage group was the difference from placebo statistically significant, however (P=0.01).
None of the differences in outcomes were statistically significant in an intent-to-treat analysis, which included the 92 patients who failed to complete the 8-week study, failed drug screens, were rated by an evaluator who had lost certification, or otherwise deviated from the study protocol.
Drug-related adverse effects were more numerous with increasing dosage, the investigators reported. Most common were somnolence, dizziness, and headache. No lab or cardiac abnormalities were noted in any patient.
Santarelli and colleagues did not appear concerned about the lack of efficacy in the high-dose group. This result was consistent with findings in animal models, they indicated. One explanation is that overloading NMDA receptors with glycine causes the receptors to withdraw inside cell membranes, resulting in diminution of receptor activity. Another possibility is that overexcitement of NMDA alters activity in other neurotransmitter pathways that ultimately counteracts the intended effect.
Roche has commenced six phase III trials of bitopertin with longer treatment intervals and omitting the higher dosage. Initial results in two of these trials failed to match the phase II findings, according to Roche, but the firm said it would await completion of the others before deciding on whether to pursue marketing approvals.
The bitopertin study was funded by Roche. Most authors including Santarelli were Roche employees.
The alcohol study was funded by the Wellcome Trust and government and university sources in Spain. All authors declared they had no relevant financial interests.
The epilepsy study was funded by U.S. and Australian government grants. All authors declared they had no relevant financial interests.
By John Gever, Deputy Managing Editor, MedPage Today
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