Роль минеральных веществ в патогенезе психических расстройств

Early studies showed that women affected by chronic depression sometimes have copper, zinc, and cesium deficiencies [37,38]. Later studies suggest that the presence of depression and other neuropsychiatric symptoms is due to the deposit of copper in the central nervous system [39]. Eggers et al. [40] used SPECT to demonstrate a reduction in thalamichypothalamic presynaptic dopamine and serotonin transporters due to the accumulation of copper. There was a negative correlation between the density of presynaptic dopamine transporters and the severity of depression as assessed using the Hamilton Rating Scale for Depression.

It was recently hypothesized that trace elements play an important role in the pathogenesis of

bipolar disorders by causing neurodegeneration [41]. Moreover, essential elements like vanadium have been implicated as a causative factor for bipolar mood disorder, while elevated vanadium and molybdenum levels have been reported in serum samples from bipolar mood disorder patients [41]. This latter study showed, using DSM-IV standard diagnostic criteria and classification into types I, II, and V according to the concept of Young and Klerman, that Na, K, P, Cu, Al, and Mn were elevated significantly in Bipolar I (Mania) (P < 0.001). In Bipolar II hypomania, Na, S, Al, and Mn were increased significantly (P < 0.02), while in Bipolar II depression, Na, K, Cu, and Al were increased significantly (P < 0.001). Finally, in Bipolar V, Na, Mg, P, Cu, and Al were increased significantly (P < 0.002) compared to a control group [41]. A recent study by Gonzales-Estecha and colleagues [21] found higher serum copper and zinc, blood lead and cadmium, and urine lead, cadmium, and thallium concentrations in patients diagnosed with bipolar disorders compared to a control group.

Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mostly by inducing lipid peroxidation in membranes, proteins and genes [42]. It has been hypothesized that these pathological processes occur in critical brain circuits that regulate affective functioning, emotions, motoric behavior and pleasure involved in bipolar disorder (BD) [43,44].

The brain is particularly vulnerable to oxidative damage since it contains large amounts of polysaturated fatty acids and possesses low antioxidant capacity [45]. Several studies have demonstrated altered OxS parameters in the pathophysiology and therapeutics of BD, including changes in the levels of enzymes superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS) [46]. The well-known stabilizing agent Lithium was found to limit the enzyme activity, potentially lowering hydrogen peroxide and hydroxyl radical formation. Similarly, lithium was also shown to reverse increased OxS parameters in BD [43,47]. For instance, a decline in lipid peroxidation and an increase in CAT levels were observed in valproate and lithium-treated rats [42,48]. Accumulation of copper was shown to increase oxidative stress in bivalve species [49]. In skeletal muscle of Broilers Under Heat Stress, copper decreases because of dietary Selenium, Vitamin E, and their combination with an increase in antioxidant defense [50]. In humans accumulation of copper was associated with oxidative stress in allergic asthma patients, and introduction of nutritional supplement therapy accompanies improved oxidative stress, immune response, pulmonary function, and decrease in copper plasma levels [51]. On the other hands copper levels were elevated in several brain areas in a degenerative disease such as Niemann-Pick C [52]. Interestingly, Nieman-Pick C disease was specifically indicated to be associated with Bipolar Disorders [53]. If the results of our study are further confirmed, it will lend significant support to the hypothesis that minerals such as copper play an etiological role in psychiatric disorders, and WD may serve as a pathogenic model for the bipolar disorder. 

Bipolar disorders and Wilson’s disease

Ботулотоксин и эмоции

This small, controlled study suggests that paralysis of the "frowning" muscle might be effective.
Several classic studies demonstrate that activation of specific facial muscles (e.g., clenching a pencil between one's teeth to activate the smiling muscles) can alter mood. These researchers examined whether clinical improvement is associated with decreased depressive facial expression through the use of botulinum toxin type A in the glabellar region.
Inclusion criteria were ongoing major depressive disorder, Hamilton Rating Scale for Depression (HRSD) score of 15 or higher, and a moderate-to-severe vertical glabellar line during maximum frowning. Patients were taking one or two antidepressants or had not responded to at least one previous antidepressant. The investigators assessed 263 patients for eligibility and accepted 30 (23 women; average age, 51; mean HRSD, 20; illness duration, 16 years; current episode, 29 months). Patients received injections of botulinum toxin or placebo and were assessed biweekly.
To mask treatment assignment, patients wore caps covering the affected area during assessments. HRSD scores significantly improved at 6 weeks in the active group (HRSD change, –10.07 vs. –1.73 with placebo; response rate [50% decrease in HRSD], 60% vs. 13%). The treatment was identified by 60% of raters and 90% of subjects. Opinion about the cosmetic change was not linked to response.
Comment: These thought-provoking results raise a skeptical eyebrow. Very few screened subjects were enrolled, and group assignment was obvious. The authors claim that exclusion rates were high because of psychiatric comorbidity, medication history, and patient refusal (recruitment information did not identify the protocol). Still, in these subjects with moderate and chronic major depressive disorder unresponsive to at least one medication, botulinum toxin demonstrated an effect similar to medication and greater than transcranial magnetic stimulation. The results appear to confirm the connection between facial expression and feelings. Botulinum toxin may have a therapeutic role in depression, although larger clinical trials are necessary to confirm this initial finding.

Put On a Happy Face: Botulinum Toxin for Depression?

Тиоридазин и онкология

By testing hundreds of compounds, they identified nearly 20 potential cancer stem cell specific drugs.
The one that appeared most promising is an antipsychotic drug, thioridazine, which combats the symptoms of schizophrenia by targeting dopamine receptors in the brain. But concerns about side effects of the drug, brand name Mellaril, have meant that far fewer people with schizophrenia are prescribed the drug than newer antipsychotic medications.
Researchers say thioridazine doesn’t appear to kill cancer stem cells, but rather encourages them to differentiate, thus exhausting the pool of self-renewing cells.
Investigators discovered thioridazine kills leukemia stem cells without affecting normal blood stem cells by comparing the proteins in leukemia versus normal blood cells.
Furthermore, leukemia cells, but not normal blood stem cells, express a dopamine receptor on their surfaces. This finding is supported by the discovery of dopamine receptors on some breast cancer stem cells.
“This gives us some explanation,” Bhatia said. It also suggests that dopamine receptors might serve as a biomarker for rare, tumor-initiating cells.
In light of the findings, Bhatia’s team is already planning for a clinical trial of the FDA-approved thioridazine in combination with standard anti-cancer drugs for adult acute myeloid leukemia.

 Drug Used for Schizophrenia May Check Cancer

Режим сна в предупреждении обострений БАР с быстрой сменой фаз

BACKGROUND:
The modern practice of using artificial light to extend waking activities into the nighttime hours might be expected to precipitate or exacerbate bipolar illness, because it has been shown that modifying the timing and duration of sleep can induce mania in susceptible individuals. With this possibility in mind, we treated a patient with rapidly cycling bipolar illness by creating an environment that was likely to increase and to stabilize the number of hours that he slept each night.
METHODS:
We asked the patient to remain at bed rest in the dark for 14 hours each night (later this was gradually reduced to 10 hours). Over a period of several years, his clinical state was assessed with twice-daily self-ratings, once-weekly observer ratings, and continuous wrist motor activity recordings. Times of sleeping and waking were recorded with sleep logs, polygraphic recordings, and computer-based event recordings.
RESULTS:
The patient cycled rapidly between depression and mania and experienced marked fluctuations in the timing and duration of sleep when he slept according to his usual routine, but his sleep and mood stabilized when he adhered to a regimen of long nightly periods of enforced bed rest in the dark.
CONCLUSIONS:
Fostering sleep and stabilizing its timing by scheduling regular nightly periods of enforced bed rest in the dark may help to prevent mania and rapid cycling in bipolar patients.

 Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

Индуцированная сибутрамином мания как дебют биполярного аффективного расстройства

Background
Sibutramine, used in obesity treatment, has been associated with many neuropsychiatric side effects including hypomanic and manic episodes. Hypomanic or manic episodes related to sibutramine treatment were earlier reported in patients who had previous history of bipolar disorder, after sibutramine overdose, after over-the-counter product illegally containing very high dose of sibutramine, together with psychotic symptoms, in organic patient, or after interaction of sibutramine with other drugs.
Case presentation
We report the first case of a patient with clear manic episode, after treatment with recommended dose of sibutramine, without previous history of mood disorders, organic changes or drug interactions, that was followed by episode of depression.
Conclusion
Minimal recommended dose of sibutramine induced manic episode that was the first manifestation of bipolar disorder. The manic episode, associated with sibutramine treatment, was induced in a person without previous history of mood disorders. Potential risks associated with the treatment of obesity using sibutramine warn physicians to be alert not only to common and cardiovascular but also to psychiatric adverse effects. A careful assessment of patient's mental state and detailed psychiatric family history should be done before sibutramine treatment. In patients with a family history for bipolar disorder the use of even minimal dose of sibutramine should be contraindicated.

 Sibutramine-induced mania as the first manifestation of bipolar disorder.

Потенцирование антидепрессивного действия сертралина целекоксибом

Background
It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD).
Methods
In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale—17 items (Ham-D) score ≥ 18 were randomly assigned to either celecoxib (200 mg twice daily) or placebo in addition to sertraline (200 mg/day) for 6 weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6.
Results
The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI) = 0.42(0.30 to 0.55) pg/ml, t(35) = 6.727, P < 0.001) as well as Ham-D scores (mean difference (95%CI) = 3.35(1.08 to 5.61), t(38) = 2.99, P = 0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P = 0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r = 0.378, P = 0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r = 0.673, P < 0.001).
Limitations
We did not measure other inflammatory biomarkers.
Conclusions
We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant

 Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: Randomized double-blind placebo-controlled study

Оценка качества ремиссии и шкала Гамильтона

Objective: In treatment studies of depression, remission is typically defined narrowly, based on scores on symptom severity scales. Patients treated in clinical practice, however, define the concept of remission more broadly and consider functional status, coping ability, and life satisfaction as important indicators of remission status. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined how many depressed patients in ongoing treatment who scored in the remission range on the 17-item Hamilton Depression Rating scale (HDRS) did not consider themselves to be in remission from their depression. Among the HDRS remitters, we compared the demographic and clinical characteristics of patients who did and did not consider themselves to be in remission.

Method: From March 2009 to July 2010, we interviewed 274 psychiatric outpatients diagnosed with DSM-IV major depressive disorder who were in ongoing treatment. The patients completed measures of depressive and anxious symptoms, psychosocial functioning, and quality of life.

Results: Approximately one-half of the patients scoring 7 and below on the HDRS (77 of 140 patients for whom self-reported remission status was available) did not consider themselves to be in remission. The self-described remitters had significantly lower levels of depression and anxiety than the patients who did not consider themselves to be in remission (P < .001). Compared to patients who did not consider themselves to be in remission, the remitters reported significantly better quality of life (P < .001) and less functional impairment due to depression (P < .001). Remitters were significantly less likely to report dissatisfaction in their mental health (P < .01), had higher positive mental health scores (P < .001), and reported better coping ability (P < .001).

Conclusions: Some patients who meet symptom-based definitions of remission nonetheless experience low levels of symptoms or functional impairment or deficits in coping ability, thereby warranting a modification in treatment. The findings raise caution in relying exclusively on symptom-based definitions of remission to guide treatment decision-making in clinical practice.

Why Do Some Depressed Outpatients Who Are in Remission According to the Hamilton Depression Rating Scale Not Consider Themselves to Be in Remission?

СДВГ и хроническая форма болезни Лайма

Dr. Young said the correlation between ADHD and CLD "is novel in the research literature. Symptoms of CLD include persistent fatigue and unexplainable generalized pain. We conclude that many individuals who are diagnosed with CLD might have ADHD (inattentive type). We believe that many are diagnosed with CLD inaccurately and that ADHD symptoms might better explain their persistent pain and fatigue," he added.
Dr. Young emphasized that there is currently "little consensus about the validity of CLD. Most clinicians agree that there is a phenomenon of acute Lyme disease, but there is no consensus about whether it is a chronic condition. I believe that patients who have these symptoms often get the diagnosis of CLD because there is no other explanation for their chronic fatigue and pain."
"Many times," Dr. Young added, "the neuropsychiatric complications associated with CLD are the most problematic for individuals. My research indicates that individuals with CLD should be evaluated for ADHD. It is unclear if treating ADHD will help these individuals' symptoms of pain and fatigue."

Chronic Lyme Disease Linked to ADHD in Adults

Риск шизофрении и чувствительность к глютену у матери

Maternal infections and other inflammatory disorders during pregnancy have long been linked to greater risk for schizophrenia in the offspring but, the Swedish and U.S. investigators say, this is the first study that points to maternal food sensitivity as a possible culprit in the development of such disorders. The findings establish a strong link but do not mean that gluten sensitivity will invariably cause schizophrenia, the investigators caution. The research, however, does suggest an intriguing new mechanism that may drive up risk and illuminate possible prevention strategies.
"Our research not only underscores the importance of maternal nutrition during pregnancy and its lifelong effects on the offspring, but also suggests one potential cheap and easy way to reduce risk if we were to find further proof that gluten sensitivity exacerbates or drives up schizophrenia risk," said study lead investigator Håkan Karlsson, M.D., Ph.D., a neuroscientist at Karolinska Institutet and former neuro-virology fellow at Johns Hopkins.
The team's findings are based on an examination of 764 birth records and neonatal blood samples of Swedes born between 1975 and 1985. Some 211 of them subsequently developed non-affective psychoses, such as schizophrenia and delusional disorders.
Using stored neonatal blood samples, the investigators measured levels of IgG antibodies to milk and wheat. IgG antibodies are markers of immune system reaction triggered by the presence of certain proteins. Because a mother's antibodies cross the placenta during pregnancy to confer immunity to the baby, a newborn's elevated IgG levels are proof of protein sensitivity in the mother.
Children born to mothers with abnormally high levels of antibodies to the wheat protein gluten had nearly twice the risk of developing schizophrenia later in life, compared with children who had normal levels of gluten antibodies. The link persisted even after researchers accounted for other factors known to increase schizophrenia risk, including maternal age, gestational age, mode of delivery and the mother's immigration status. The risk for psychiatric disorders was not increased among those with elevated levels of antibodies to milk protein.

Maternal Antibodies to Gluten Linked to Schizophrenia Risk in Children

N-ацетилцистеин в коррекции возбудимости у детей с аутизмом

Background
An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.
Methods
This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.
Results
Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2–10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).
Conclusions
Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

 A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

Повышенное содержание кинуреновой кислоты в ЦСЖ больных шизофренией

Schizophrenia patients show increased levels of kynurenic acid (KYNA) and its precursor kynurenine (KYN) in cerebrospinal fluid, researchers report.
They say that their findings provide further support for the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.
Writing in Schizophrenia Bulletin, Sophie Erhardt (Karolinska Institute, Stockholm, Sweden) and team explain: "KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and α7 nicotinic receptors."

Kynurenic acid levels increased in schizophrenia patients

Зависимость эпилептических приступов от времени суток

OBJECTIVE:
To evaluate whether the distribution of seizures throughout the day is the same in ambulatory outpatient conditions as observed in inpatient conditions.
METHODS:
We analyzed records from consecutive patients who had ambulatory EEG monitoring for 24 to 72 hours using Digitrace™ EEG recording system. The participants maintained a log of symptoms and signaled the time when symptoms occurred by pushing an event button. Additionally, automatic seizure and spike detection was performed on each record using Persyst detection software.
RESULTS:
Of 831 reports analyzed, 44 unique patients had definite ictal events. There were a total of 129 electrographic seizures (34 subclinical) with timing as follows: frontal (31), temporal (71), and generalized, posterior, or central (27). Frontal lobe seizures occurred more frequently between 12 am and 12 pm as compared to temporal lobe seizures, which occurred more frequently between 12 pm and 12 am (p = 0.017). Analysis of frontal lobe seizures revealed a cluster of 10 seizures centered at 6:33 am (range 5:15-7:30 am) with p = 0.0064. Temporal lobe seizures had a cluster of 24 seizures centered at 8:49 pm (range 6:45-11:56 pm) with p = 0.0437.
CONCLUSION:
In ambulatory outpatient conditions, electrographic seizures follow day/night patterns similar to those observed in hospital conditions. Frontal seizures occur preferentially in the early morning hours and temporal lobe seizures occur in the early evening hours.

 Diurnal pattern of seizures outside the hospital: Is there a time of circadian vulnerability?

Приверженность лечению клозапином и пролонгированными формами антипсихотиков в сравнении с пероральным олонзапином

They found an 83% lower risk for all-cause discontinuation of clozapine than for oral olanzapine (Zyprexa, Eli Lilly and Co.) treatment. "Patient adherence with clozapine and the LAI antipsychotics is much better than with oral olanzapine, which has been considered the most efficacious drug, according to the 2005 Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study," Dr. Kroken said.

... 

"This has to do with the formulation; patients allow prescribing to continue for longer on LAIs than on orals. This might also be due to...seeing a clinician every 2 weeks," said Dr. Patel.

Adherence Better With Clozapine and LAI Antipsychotics

Потенцирование антидепрессивного действия циталопрама пиоглитазоном

Thiazolidinediones have shown antidepressant effect in animal studies, as well as in some uncontrolled studies evaluating human subjects with concurrent major depressive disorder (MDD) and metabolic syndrome. Although these drugs are insulin sensitizers, they also have important anti-inflammatory, neuroprotective, and anti-excitotoxic properties. Thus, we hypothesized that they would show antidepressant effect in patients with MDD even if it was not accompanied by metabolic disturbances. In this double-blind placebo-controlled study, 40 patients with MDD (DSM-IV-TR) and Hamilton depression rating scale-17 (Ham-D) score 22 were randomized to citalopram plus pioglitazone (15 mg every 12 h) (n=20) or citalopram plus placebo (n=20) for 6 weeks. Patients were evaluated using Ham-D (weeks 0, 2, 4, 6). Repeated-measure analysis of variance (ANOVA) and analysis of covariance were used for comparison of scores between the two groups. Treatment response (50% reduction in Ham-D score), remission (Ham-D score7), and early improvement (20% reduction in Ham-D score within the first 2 weeks) were compared between the two groups using Fisher's exact test. Pioglitazone showed superiority over placebo during the course of the trial (F(1, 38)=9.483, p=0.004). Patients in the pioglitazone group had significantly lower scores at all time points than the placebo group (P<0.01). Frequency of early improvement, response (week 6), and remission was significantly higher in the pioglitazone group (95%, 95%, 45%, respectively) than in the placebo (30%, 40%, 15% respectively) group (P<0.001, <0.001, 0.04, respectively). Frequency of side effects was similar between the two groups. Pioglitazone is a safe and effective adjunctive short-term treatment in patients with moderate-to-severe MDD even in the absence of metabolic syndrome and diabetes.

Pioglitazone Adjunctive Therapy for Moderate-to-Severe Major Depressive Disorder: Randomized Double-Blind Placebo-Controlled Trial.

Аутоиммунные факторы в патогенезе обсессивно-компульсивной симптоматики

Background
Symptoms of obsessive–compulsive disorder (OCD) have been described in neuropsychiatric syndromes associated with streptococcal infections. It is proposed that antibodies raised against streptococcal proteins cross-react with neuronal proteins (antigens) in the brain, particularly in the basal ganglia, which is a brain region implicated in OCD pathogenesis.
Aims
To test the hypothesis that post-streptococcal autoimmunity, directed against neuronal antigens, may contribute to the pathogenesis of OCD in adults.
Method
Ninety-six participants with OCD were tested for the presence of anti-streptolysin-O titres (ASOT) and the presence of anti-basal ganglia antibodies (ABGA) in a cross-sectional study. The ABGA were tested for with western blots using three recombinant antigens; aldolase C, enolase and pyruvate kinase. The findings were compared with those in a control group of individuals with depression (n = 33) and schizophrenia (n = 17).
Results
Positivity for ABGA was observed in 19/96 (19.8%) participants with OCD compared with 2/50 (4%) of controls (Fisher’s exact test P = 0.012). The majority of positive OCD sera (13/19) had antibodies against the enolase antigen. No clinical variables were associated with ABGA positivity. Positivity for ASOT was not associated with ABGA positivity nor found at an increased incidence in participants with OCD compared with controls.
Conclusions
These findings support the hypothesis that central nervous system autoimmunity may have an aetiological role in some adults with OCD. Further study is required to examine whether the antibodies concerned are pathogenic and whether exposure to streptococcal infection in vulnerable individuals is a risk factor for the development of OCD.

Prevalence of anti-basal ganglia antibodies in adult obsessive–compulsive disorder: cross-sectional study