Антипсихотики второго поколения в терапии депрессии

Abstract

Purpose of review The aim of this systematic review was to examine the efficacy and safety of second-generation antipsychotics (SGAs) in nonpsychotic major depressive disorder (MDD).
Recent findings In MDD, SGA monotherapy or adjunctive therapy to conventional antidepressants showed rapid onset of antidepressant efficacy. Although maintenance data are limited, quetiapine monotherapy, risperidone adjunctive therapy, and amisulpride adjunctive therapy significantly delayed the time to relapse as compared with placebo. In general, extrapyramidal symptoms appeared to be low with SGAs, but a higher incidence of akathisia was observed with aripiprazole. An elevated risk of weight gain was observed with olanzapine–fluoxetine combination, risperidone, aripiprazole, and quetiapine compared with placebo. At present, there are insufficient data to confidently distinguish between different SGAs in the treatment of MDD. A recent meta-analysis found that adjunctive SGAs were significantly more effective than placebo, but differences in efficacy were not identified among the studied agents, nor were outcomes affected by trial duration or the method of establishing treatment resistance.
Summary Both SGA monotherapy and adjunctive therapy showed greater efficacy in the treatment of MDD than placebo, but augmentation is more widely utilized in treatment-resistant depression. Clinicians should routinely monitor for cardiometabolic side-effects and extrapyramidal symptoms during SGA therapy.

Quetiapine

The efficacy and safety of QTP-XR monotherapy in the treatment of MDD were evaluated in two 8-week, placebo-controlled RCTs.[7••,8•] In the first trial, QTP-XR 150 or 300 mg/day and duloxetine 60 mg/day were compared with placebo.[7••] All active treatment arms demonstrated significant improvement in Montgomery–Asberg Depression Rating Scale (MADRS)[27] total scores compared with that of placebo at week 6. Significant improvement in depressive symptoms occurred at the end of week 1 with both QTP-XR 150 mg/day (−8.4, P < 0.01) and 300 mg/day (−8.2, P < 0.01) compared with placebo (−6.0), but not duloxetine 60 mg/day (−6.8, P = 0.30). At study endpoint (week 6), remission rates (MADRS ≤ 8) were significantly higher in the QTP-XR 300 mg/day (32.0%, P < 0.05) and duloxetine 60 mg/day groups (31.9%, P < 0.05) vs. placebo (20.4%), but not for QTP-XR 150 mg/day (26.5%, P = 0.27).
Sulpiride and Amisulpride

Apart from QTP-XR, SLP and ASLP are the only other SGAs that have been studied as monotherapy treatment for MDD in placebo-controlled trials. A moderately sized (n = 88) study found greater reduction in the 21-item Hamilton Depression Rating Scale (HAM-D-21)[28] total score from baseline to endpoint in the SLP group (−10, P = 0.0007) than in placebo (−8). The only RCT of ASLP in the acute treatment of MDD compared a fixed dosage of ASLP 50 mg/day (n = 136) with paroxetine 20 mg/day (n = 136).[11] No statistically significant differences occurred between the two treatments, but a placebo group was not included to establish internal validity.[11] A long-term (6-month), fixed-dosage, placebo-controlled RCT in mild or moderate MDD or dysthymia compared the efficacy and safety of ASLP (50 mg/day) with imipramine (100 mg/day) and placebo.[12] Analysis of the primary outcome showed the mean change in MADRS total scores in both active treatment arms was significantly larger than that of placebo, although remission rates did not reach the level of statistical significance.

Second-generation Antipsychotics in Major Depressive Disorder: Update and Clinical Perspective

Гормонотерапия при депрессиях

Extensive preclinical studies demonstrate that estrogen can, in many ways, modulate molecular pathways involved in monoaminergic neurotransmission (serotonin [5-hydroxy-tryptamine receptors or 5-HT], norepinephrine [NE]); these systems are critical for mood and behavior regulation. Estradiol (E2) administration decreases the activity of monoamine oxidases (MAO-A and MAO-B), which are enzymes involved in 5-HT degradation; E2 also increases both isoforms of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis. Thus, E2 administration results in an overall increase in 5-HT synthesis and availability. E2 also regulates the 5-HT transporter, which plays an integral role in 5-HT reuptake from the synaptic cleft to the pre-synaptic neuron. Furthermore, by downregulating 5-HT1a autoreceptors and upregulating 5-HT2a receptors, E2 increases the amount of serotonin found in the synapse and increases the amount available for postsynaptic transmission. E2 is capable of inducing antidepressant effects in ovariectomized rats when administered in combination with subdoses of fluoxetine, which suggests that E2 can also augment antidepressant agents. In sum, estrogen appears to work via different pathways that ultimately result in increased serotonin production and transmission. Similarly, estrogens increase NE availability by decreasing expression of MAOs and increasing the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthetic pathway of catecholamine.

Clinically, E2 administration to depressed perimenopausal and early postmenopausal women demonstrated antidepressant effects of similar magnitude to that observed with antidepressant agents. Randomized, double-blind, placebo-controlled studies reported significantly greater reduction in depressive symptoms with the use of transdermal estradiol (17β-estradiol, 50-100 µg), compared to placebo.[3] In some studies, the antidepressant effects of estrogen were observed even in the absence of concomitant vasomotor symptoms.[4] Notably, studies on E2 therapy for older, postmenopausal women suffering from depression resulted in small, nonsignificant reduction in depressive symptoms. Taken together, these observations suggest that: 1) estrogen’s antidepressant effect may have a “critical window” or optimal timing, possibly during the menopause transition and early postmenopausal years; and 2) the potential benefits of E2 therapy for the improvement of mood symptoms may occur independent from changes or improvement of vasomotor symptoms. In sum, preclinical and clinical evidence suggest that estrogen-based therapies can contribute to greater therapeutic responses and potentially boost the response to traditional antidepressant agents, along with well-established benefits for vasomotor, sexual, and other menopause-related symptoms.

HT in Managing Depression in a Patient Using SSRIs

терапия серотонинового синдрома

In general, treatment of SS first involves discontinuing the offending drug(s) and providing the patient with supportive care. Many mild-to-moderate SS cases are self-limiting and usually resolve within 24 to 72 hours.[19] Resolution of more severe cases will likely take much longer. In such cases, supportive care, drug discontinuation, and administration of medication (e.g., diazepam 5 mg IV to reduce hypertonicity and neurologic excitability) may be sufficient to resolve mild symptoms.[2,13,36] Patients with severe symptoms may need sedation, paralyzation, and intubation.

Administration of drugs with serotonin antagonist properties, such as cyproheptadine and chlorpromazine, has been utilized in a few patients.[4,16,18] Cyproheptadine 4 mg orally is the most widely used antidote for SS.[36] Although increased body temperature is common in patients with severe SS, antipyretic therapy usually is not recommended. This is because the fever that occurs with SS is caused by excessive muscular activity, not a change in the hypothalamic temperature set point.[2]

Drug-Induced Serotonin Syndrome: Clinical Signs and Symptoms

Алкоголизм функционально хорошо заменяется депрессивным состоянием партнера. В системной модели "Спасатель" описывается динамика гиперфункциональности и гипофункциональности в семье: тот, кто спасает - гиперфункционал. Рядом с гиперфункционалом для прочных отношений должен быть гипофункционал. Гипофункциональность задается не только алкоголизмом, наркоманией, но и депрессией. В функциональных семьях так же может развиваться динамика гипер- и гипофункциональности. Например, жена может давать мужу сообщение, что он не достаточно эффективен просто тем, что она сама очень функциональна. Он только соберется что-то сделать, а она уже все сделала. Она - быстрее, энергичнее, и у него формируется ощущение несостоятельности. Один мой клиент рассказывал мне, что в своем первом браке он очень много делал всего по дому. Его первая жена была медлительная и очень нетребовательная. Во втором браке он ничего не делал по хозяйству. Говорил: "Ничего не хочется делать. Жена сама все лучше и быстрее делает, и вообще она всегда недовольна тем, что я делаю". Понятно, что жена была так же недовольна и тем, что муж ничего не делал, не был включен в семейную жизнь.

Семейные мифы в практике системной семейной психотерапии

Непереносимость глютена и шизофрения

Celiac disease (CD) and schizophrenia have approximately the same prevalence, but epidemiologic data show higher prevalence of CD among schizophrenia patients. The reason for this higher co-occurrence is not known, but the clinical knowledge about the presence of immunologic markers for CD or gluten intolerance in schizophrenia patients may have implications for treatment. Our goal was to evaluate antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group. AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race. Linear regression was used to predict PANSS scores from AGA and tTG antibodies adjusting for age, gender, and race. Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group (chi(2) = 1885, df = 2, P < .001.) Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group (chi(2) = 392.0, df = 2, P < .001). Adjustments for sex, age, and race had trivial effects on the differences. Regression analyses failed to predict PANSS scores from AGA and tTG antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to CD and gluten sensitivity.

Prevalence of Celiac Disease and Gluten Sensitivity in the United States Clinical Antipsychotic Trials of Intervention Effectiveness Study Population.

Синдром хронической усталости и вирус XMRV

A set of papers out today in Retrovirology (1,2,3,4) claim that many previous studies claiming to have found the virus haven't actually been detecting XMRV at all.

Here's the rub. XMRV is a retrovirus, a class of bugs that includes HIV. Retroviruses are composed of RNA, but they can insert themselves into the genetic material of host cells as DNA. This is how they reproduce: once their DNA is part of the host cell's chromosomes, that cell is ends up making more copies of the virus.

But there are lots of retroviruses out there, and there used to be yet others that are now extinct. So bits of retroviral DNA are scattered throughout the genome of animals. These are called endogenonous retro-viruses (ERVs).

XMRV is extremely similar to certain ERVs found in the DNA of mice. And mice are the most popular laboratory mammals in the world. So you can see the potential problem: laboratories all over the world are full of mice, but mouse DNA might show up as "XMRV" DNA on PCR tests.

XMRV - Innocent on All Counts?

Длительность лечения тревожного расстройства

Relapse rates after 12 months of venlafaxine XR treatment were 6.7% for patients who were taking venlafaxine XR for the full 18 months, 20.0% for patients taking placebo for 12 months (months 6 to 18), and 32.3% for placebo patients who switched at month 12 to placebo (P < .14).

The study also found that patients treated with venlafaxine XR for 12 months before being shifted to placebo experienced a lower relapse rate (32.4%) than patients shifted to placebo after taking venlafaxine XR for only 6 months (53.7%; P < .03).

Chronic Anxiety Requires Long-Term Treatment to Prevent Relapse

Женьшень и когнитивные функции

There is a lack of convincing evidence to show a cognitive-enhancing effect of Panax ginseng in healthy people and no high-quality evidence about its efficacy in patients with dementia, according to a report published online December 8 in the Cochrane Database of Systematic Reviews.

"Ginseng appeared to have some beneficial effects on cognition, behavior, and quality of life. However, at present, recommendations of continuing taking or stopping cannot be made due to lack of high-quality evidence," first study author JinSong Geng, of the Evidence-based Medicine Center, Medical School of Nantong University in Jiangsu, China, told Medscape Medical News.

Evidence That Ginseng Boosts Brain Function 'Not Convincing'

Циклосерин и аутизм

Researchers have launched a pilot clinical trial of a new medication aimed at relieving the sociability problems of adolescent and young adult patients with autism spectrum disorders (ASD).

The medication used, D-Cycloserine, originally was developed to treat tuberculosis, but previous studies showed, by chance, that it might change social behavior.

New Drug May Ease Social Impairment of Autism

Когнитивное снижение при шизофрении

The cholinergic system

In the 1970s, it was found that Alzheimer disease was caused primarily by the degeneration of acetylcholine (ACH) or cholinergic neurons that emanate from the nucleus basalis of Meynert. This landmark finding was on the one hand startling, since it had been thought that more widespread neurochemical deficits would be found. On the other hand, it was consistent with decades of work that showed that anticholinergic medications disrupted cognitive functions and, in particular, memory in nonpatient populations. Regarding schizophrenia, a small but compelling literature indicates that anticholinergics counter the therapeutic action of neuroleptics.14 Findings from recent clinical trials indicate that both muscarinic and nicotinic agonists hold promise in the treatment of cognitive symptoms of schizophrenia.
While awaiting new cholinergic agonists, we can begin to address the cholinergic deficit in schizophrenia. First is to “do no harm” by avoiding the use of highly anticholinergic regimens that can exacerbate cognitive deficits. For example, if the use of anticholinergics to treat extrapyramidal syndrome (EPS) appears to be exacerbating cognitive symptoms, consider amantadine, which treats EPS but is not an anticholinergic. In a double-blind, cross-over study, Silver and Geraisy17 showed that biperiden (an anticholinergic), but not amantadine, interferes with memory and, in particular, visual memory.

It is extremely important to help those with schizophrenia to stop smoking; bear in mind, however, that they may smoke because nicotine improves their cognitive symptoms. While the smoking itself should cease, nicotine replacement therapy may need to be continued indefinitely to prevent a worsening of cognition.

D1 dopamine–mediated processes

A link has been shown between prefrontal dysfunction and the cognitive deficits observed in schizophrenia.18,19 Goldman–Rakic20 has suggested that disruption of D1 dopamine receptor activity can contribute to the cognitive symptoms of schizophrenia, while stimulation of the D1 dopamine receptor improves cognition.21

Modafinil has been found to improve short–term verbal memory span, visual memory, and spatial planning in patients with chronic schizophrenia. It is reasonable to hypothesize that it does this, at least in part, by stimulating D1 dopamine receptors.22

Hypofunction of the NMDAglutamate system

In the 1980s, phencyclidine (PCP), “angel dust,” was a widely used recreational drug of abuse. Some people were brought to psychiatric emergency departments with schizophrenia–like symptoms, including positive, negative, and cognitive symptoms. The hypothesis that schizophrenia may be a result of hypofunction of the NMDA glutamate system emerged when it was found that PCP blocked calcium efflux through channels controlled by NMDA glutamate receptors.

In the NMDA glutamate system, glutamate binding to a subset of receptors leads to the opening of the calcium channel, but only if a second site is simultaneously occupied by either glycine or D–serine, both of which are released into the synapse by astrocytes. Glycine’s action is terminated when it binds to a glycine transporter protein and is brought back to the astrocytes where it is oxidized. High doses of dietary glycine added to antipsychotic regimens can lead to clinical improvement, but in clinical practice, glycine–induced nausea limits its utility.23

Recently, another promising strategy has emerged. Glycine levels in the synapses can be raised by glycine transport inhibitors that prevent glycine from entering the surroundingastrocytes. Consequently, more glycine remains in the synapse.

Several glycine transport inhibitors are presently in or are entering clinical trials. One promising candidate is N–methylglycine, or sarcosine.24 Preliminary studies indicate that added to antipsychotics, 1 to 2 g of sarcosine per day can lead to significant improvement in positive, negative, and cognitive symptoms.

Cognitive Symptoms in Schizophrenia Recognizing and Treating Cognitive Deficits in Schizophrenia

антидепрессивный эффект эйкозапентаеновой кислоты

In fact, only eicosapentaenoic acid (EPA) — and not docosahexaenoic acid (DHA) — is associated with mood improvement in patients with depression, concluded lead study author John M. Davis, MD, research professor at the University of Illinois in Chicago.

The meta-analysis of 15 randomized, double-blind, placebo-controlled studies clarifies which type of omega-3 fatty acid is effective for depression and why previous findings on the antidepressant effects of omega-3 fatty acids have been contradictory, said Dr. Davis at a press conference.

Omega-3 fatty acids are not synthesized by the body and therefore must be consumed in food (primarily fish and nuts) or supplements. In food, EPA and DHA are found together in a 1:1 ratio, but supplements can contain either fatty acid or a combination of both, he said.

The study concluded that an EPA-predominant formulation is necessary for the full therapeutic antidepressant action, whereas the DHA-predominant formulation has little antidepressant efficacy.

Not All Omega-3s Equal When It Comes to Antidepressant Effects

Акампросат в лечении тревожных расстройств

BACKGROUND: Glutamate is a major excitatory neurotransmitter, while {gamma}-aminobutyric acid (GABA) is a predominant inhibitory neurotransmitter in the central nervous system. This GABA-glutamate imbalance is thought to play a role in the development of anxiety. Acamprosate calcium is thought to restore this chemical imbalance in alcohol withdrawal.

OBJECTIVE: To examine acamprosate calcium as augmentation therapy for treatment of anxiety.

METHODS: This 8-week, open-label study was designed to evaluate patients with anxiety who were stable on current medications (selective serotonin-reuptake inhibitors and serotonin-norepinephrine-reuptake inhibitors) but still symptomatic. Acamprosate was dosed at 1998 mg/day. Assessments included the Hamilton Rating Scale for Anxiety (HAM-A) and the Hospital Anxiety and Depression Scale.

RESULTS: Thirteen patients enrolled in the study and received study medication. Acamprosate reduced anxiety symptoms (mean HAM-A score reduction to 8.87 from a baseline of 20). Sixty-two percent of patients receiving acamprosate achieved remission (HAM-A score ≤7). Modal dose was 1998 mg/day (range 999-1998). The most commonly reported adverse events were nausea (n = 1), gastrointestinal upset (n = 1), and increased dream activity (n = 1).

CONCLUSIONS: Acamprosate calcium may be effective augmentation therapy in patients with treatment-resistant anxiety.

Acamprosate Calcium as Augmentation Therapy for Anxiety Disorders

Депривация сна

Methods

There are two methods of using sleep deprivation as a treatment for depression: total or partial deprivation.

Partial deprivation - sleeping the first half of the night only, and waking up halfway through - proved more effective than going to sleep later, or sleeping only the second half of the night. It is thought that partial sleep deprivation, sleeping up to 4 hours a night, will have the same antidepressant benefits as total sleep deprivation. Whereas with total sleep deprivation, the benefits are felt the following day, but are not long-lasting, sleeping four hours can be done continuously, over several days or even weeks, so naturally the benefits here are superior.

Even in patients with bipolar disorder can benefit. Research shows patients with bipolar disorder after sleep deprivation, are pulled from their depressed state to manic state. Manic states can cause sleep deprivation, lasting weeks and even months, so the cycle continues. The patient feels great, lighter in mood, and feel no need for sleep. Of course one should limit this, because of other health risks in prolonged sleep deprivation. Partial deprivation, up to 4 hours sleep is definitely the way to go for long-term treatment.

The ideal way to try for yourself, seems to be to stay awake a full night the first night, then limit yourself to 4 hours a night after that. Try this for a week or two, and see how you feel. I think in most cases, you will have positive results.

If you know someone suffering with severe depression, who barely has energy to talk to you, and no matter how you try to animate them, you have no success, try visiting them in the evening and keeping them awake all night. You will find the next morning their mood will be elevated, they will be more lucid and talkative, and more likely to want to move around and do things. Try then to convince them to use an alarm clock and wake themselves up after only four hours, they'll see for themselves how much better they feel.

The optimum time for sleep appears in some studies, to be from 10pm-2am, 11pm-3am, or12-4 am, underlining the fact that sleeping only the first half of the night provides the best results. In other reports, however, 2-6am 3-7am was optimal. It would depend presumably on your normal bedtime.

Sleep deprivation treatment was popular in the 1970s, but with the discovery of new and effective antidepressant medications, it was soon deemed old-fashioned and unhelpful. Nowadays doctors are reconsidering and endorsing this treatment, finding it helpful even alongside these medications, as the body seemed to accept medication more easily. Many psychiatrists were convinced by remarkable transformations of severely depressed, psychotic and even suicidal patients, back to relative normality after only a few hours. Antidepressant medication alongside sleep deprivation, has proven to help prevent relapse into the depressed state, although these studies are still ongoing.

Sleep Deprivation as Cure for Depression

Психоз при потенцировании дулоксетина арипипразолом

"Ms. L" was a 49-year-old woman with chronic depression and postoperative cellulitis following a bunion excision. She was evaluated on the medical unit. She endorsed depressive symptoms, auditory hallucinations, and suicidal thoughts. The patient had previously attempted suicide twice by drug overdose. Her most recent suicide attempt was 7 months prior. Previous responses to sertraline and citalopram were poor. At the time of assessment on the medical unit, she was receiving duloxetine (40 mg twice daily), aripiprazole (1 mg/day), clonazepam (1 mg twice daily), and amoxicillin/clavulanate (850 mg twice daily).

The patient was started on duloxetine 7 months before. Ten days prior to admission, her primary care physician had started her on aripiprazole (2 mg/day) for augmentation. She denied a history of psychotic symptoms and drug or alcohol abuse as well as a family history of psychosis.

Three days after starting aripiprazole, Ms. L reported auditory hallucinations. She was paranoid regarding her ex-husband. She described command hallucinations from the devil, who meant to harm her, and could also hear God's voice encouraging her not to listen to the devil. She experienced concurrent onset of suicidal ideation with no plan. She was fully oriented, with no evidence of confusion. Aripiprazole was reduced to 1 mg/day, which led to amelioration of her hallucinations. However, her suicidal thoughts and paranoid beliefs persisted.

The psychiatric consultant decided to discontinue aripiprazole, leading to rapid and complete resolution of the patient's psychotic symptoms and suicidal ideation. Her ongoing depression was managed with duloxetine (60 mg twice daily).

New-Onset Psychosis and Emergence of Suicidal Ideation With Aripiprazole

Evidence supporting antiepileptics for mood disorders and schizophrenia

Medication	Bipolar disorder			Major depressive disorder	Schizophrenia
	Mania	Depression	Maintenance
Carbamazepine					(aggression, impulsivity)
Lamotrigine					(adjunct to clozapine)
Valproate					(aggression, impulsivity)
Gabapentin
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Zonisamide
	: strong evidence supporting efficacy;
	: moderate evidence supporting efficacy;
	: weak evidence supporting efficacy
Source: For an extensive bibliography of studies that support these recommendations, see this article at CurrentPsychiatry.com

Table 2
Off-label use of antiepileptics for various psychiatric disorders

Condition/disorder	Possible medication(s)*
Alcohol withdrawal/relapse prevention	Carbamazepine, topiramate, valproate
Benzodiazepine withdrawal	Carbamazepine, valproate
Binge eating disorder	Topiramate, zonisamide
Bulimia nervosa	Topiramate
Drug dependence/abstinence	Carbamazepine, lamotrigine, topiramate, tiagabine
Generalized anxiety disorder	Pregabalin, tiagabine
Obesity	Lamotrigine, topiramate, zonisamide
Panic disorder	Valproate
Posttraumatic stress disorder	Lamotrigine
Social phobia	Gabapentin, pregabalin
* Based on small randomized controlled trials, open-label trials, or case reports. Further investigation in large systematic trials is needed

Explain to patients taking topiramate or zonisamide that increasing their fluid intake will significantly reduce kidney stone risk

The FDA recently announced a warning of a risk of aseptic meningitis with lamotrigine.11 In 40 reported cases, symptoms—headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia, and myalgias—occurred between 1 and 42 days of treatment and typically resolved after lamotrigine was withdrawn. In 15 patients in whom lamotrigine was re-initiated, meningitis symptoms returned quickly and with greater severity.

Antiepileptics for psychiatric illness: Find the right match

Статины, холестерин и аффективные расстройства

New research into cholesterol-lowering statin drugs and serotonin-1A receptors may help explain the relationships between cholesterol levels and symptoms of anxiety and depression.

Shrivastava and colleagues1 explored the effect of chronic cholesterol depletion induced by mevastatin on the function and dynamics of the human serotonin-1A receptors stably expressed in animal cells. Statins are competitive inhibitors of HMG-CoA reductase, the key rate-limiting enzyme in cholesterol biosynthesis.

Statins, Cholesterol Depletion—and Mood Disorders: What’s the Link?

CYR-101

Cyrenaic Pharmaceuticals Inc. (“Cyrenaic”), a private drug development company focused on the treatment of CNS disorders, today announced Phase IIa clinical results for CYR-101, its novel investigational drug for the treatment of schizophrenia. The results from the study showed that the drug alleviated the symptoms of the disease, including the negative and cognitive symptoms.

Cyrenaic Pharmaceuticals Reports Improvement of Negative Symptoms and Cognition in Schizophrenia Patients Treated with CYR-101

Инфекционная теория шизофрении: вирус HERV-W

By the 1980s he began working with Robert Yolken, an infectious-diseases specialist at Johns Hopkins University in Baltimore, to search for a pathogen that could account for these symptoms. The two researchers found that schizophrenics often carried antibodies for toxoplasma, a parasite spread by house cats; Epstein-Barr virus, which causes mononucleosis; and cytomegalovirus. These people had clearly been exposed to those infectious agents at some point, but Torrey and Yolken never found the pathogens themselves in the patients’ bodies. The infection always seemed to have happened years before.

Torrey wondered if the moment of infection might in fact have occurred during early childhood. If schizophrenia was sparked by a disease that was more common during winter and early spring, that could explain the birth-month effect. “The psychiatrists thought I was psychotic myself,” Torrey says. “Some of them still do.”

While Torrey and Yolken were chasing their theory, another scientist unwittingly entered the fray. Hervé Perron, then a graduate student at Grenoble University in France, dropped his Ph.D. project in 1987 to pursue something more challenging and controversial: He wanted to learn if new ideas about retroviruses—a type of virus that converts RNA into DNA—could be relevant to multiple sclerosis.

Robert Gallo, the director of the Institute of Human Virology at the University of Maryland School of Medicine and co­discoverer of HIV, had speculated that a virus might trigger the paralytic brain lesions in MS. People had already looked at the herpes virus (HHV-6), cytomegalovirus, Epstein-Barr virus, and the retroviruses HTLV-1 and HTLV-2 as possible causes of the disease. But they always came up empty-handed.

Perron learned from their failures. “I decided that I should not have an a priori idea of what I would find,” he says. Rather than looking for one virus, as others had done, he tried to detect any retrovirus, whether or not it was known to science. He extracted fluids from the spinal columns of MS patients and tested for an enzyme, called reverse transcriptase, that is carried by all retroviruses. Sure enough, Perron saw faint traces of retroviral activity. Soon he obtained fuzzy electron microscope images of the retrovirus itself.

By the time Perron made his discovery, Torrey and Yolken had spent about 15 years looking for a pathogen that causes schizophrenia. They found lots of antibodies but never the bug itself. Then Håkan Karlsson, who was a postdoctoral fellow in Yolken’s lab, became interested in studies showing that retroviruses sometimes triggered psychosis in AIDS patients. The team wondered if other retroviruses might cause these symptoms in separate diseases such as schizophrenia. So they used an experiment, similar to Perron’s, that would detect any retrovirus (by finding sequences encoding reverse transcriptase enzyme)—even if it was one that had never been catalogued before. In 2001 they nabbed a possible culprit. It turned out to be HERV-W.

Several other studies have since found similar active elements of HERV-W in the blood or brain fluids of people with schizophrenia. One, published by Perron in 2008, found HERV-W in the blood of 49 percent of people with schizophrenia, compared with just 4 percent of healthy people. “The more HERV-W they had,” Perron says, “the more inflammation they had.” He now sees HERV-W as key to understanding many cases of both MS and schizophrenia. “I’ve been doubting for so many years,” he says. “I’m convinced now.”

Through this research, a rough account is emerging of how HERV-W could trigger diseases like schizophrenia, bipolar disorder, and MS. Although the body works hard to keep its ERVs under tight control, infections around the time of birth destabilize this tense standoff. Scribbled onto the marker board in Yolken’s office is a list of infections that are now known to awaken HERV-W—including herpes, toxoplasma, cytomegalovirus, and a dozen others. The HERV-W viruses that pour into the newborn’s blood and brain fluid during these infections contain proteins that may enrage the infant immune system. White blood cells vomit forth inflammatory molecules called cytokines, attracting more immune cells like riot police to a prison break.

In one experiment, Perron isolated HERV-W virus from people with MS and injected it into mice. The mice became clumsy, then paralyzed, then died of brain hemorrhages. But if Perron depleted the mice of immune cells known as T cells, the animals survived their encounter with HERV-W. It was an extreme experiment, but to Perron it made an important point. Whether people develop MS or schizophrenia may depend on how their immune system responds to HERV-W, he says. In MS the immune system directly attacks and kills brain cells, causing paralysis. In schizophrenia it may be that inflammation damages neurons indirectly by overstimulating them. “The neuron is discharging neurotransmitters, being excited by these inflammatory signals,” Perron says. “This is when you develop hallucinations, delusions, paranoia, and hyper-suicidal tendencies.”

Gene studies have failed to provide simple explanations for ailments like schizophrenia and MS. Torrey’s theory may explain why. Genes may come into play only in conjunction with certain environmental kicks. Our genome’s thousands of parasites might provide part of that kick.

“The ‘genes’ that can respond to environmental triggers or toxic pathogens are the dark side of the genome,” Perron says. Retroviruses, including HIV, are known to be awakened by inflammation—possibly the result of infection, cigarette smoke, or pollutants in drinking water. (This stress response may be written into these parasites’ basic evolutionary strategy, since stressed hosts may be more likely to spread or contract infections.) The era of writing off endogenous retroviruses and other seemingly inert parts of the genome as genetic fossils is drawing to an end, Perron says. “It’s not completely junk DNA, it’s not dead DNA,” he asserts. “It’s an incredible source of interaction with the environment.” Those interactions may trigger disease in ways that we are only just beginning to imagine.

Torrey and Yolken hope to add a new, more hopeful chapter to this story. Yolken’s wife, Faith Dickerson, is a clinical psychologist at Sheppard Pratt Health System in Baltimore. She is running a clinical trial to examine whether adding an anti-infective agent called artemisinin to the drugs that patients are already taking can lessen the symptoms of schizophrenia. The drug would hit HERV-W indirectly by tamping down the infections that awaken it. “If we can treat the toxoplasmosis,” Torrey says, “presumably we can get a better outcome than by treating [neurotransmitter] abnormalities that have occurred 14 steps down the line, which is what we’re doing now.”

The Insanity Virus

изотретионин, депрессии, суицид, акне

"Isotretinoin (13-cis-retinoic acid) has been used since the 1980s to treat severe recalcitrant nodular acne with good effect, but case reports and spontaneous reporting of adverse drug reactions have suggested an association between isotretinoin, depression, and suicidal behaviour," write Anders Sundström, from the Karolinska Institute in Stockholm, Sweden, and colleagues. "Observational studies have had conflicting results, however."

Severe acne is associated with the risk for suicide attempt even before treatment with isotretinoin was started, although the risk is increased during treatment and up to 6 months afterward, according to the results of a retrospective Swedish cohort study reported online first November 12 in the BMJ.

Severe Acne Linked to Suicide Risk Even Before Treatment Is Started

Раннее вмешательство при высоком риске психоза

Antipsychotics and cognitive therapy don't appear to help youth at ultra high risk for psychosis, according to an interim analysis of a small randomized trial.

But the study was underpowered, and it's still unclear whether early intervention can help prevent full-blown psychotic disorders in youth with putative prodromal symptoms, according to Dr. Alison R. Yung, of Orygen Research Center and the University of Melbourne in Victoria, Australia, and colleagues.

At 6 Months, Unclear If Early Intervention for Psychosis Works

Механиз атипичного действия антипсихотиков, fast off

Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics’ mechanism of action and how it differs from that of the more typical drugs. Method: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Results: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Conclusion: Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. Relevance: The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.

Atypical Antipsychotics: Mechanism of Action

Посмертные исследования больных шизофренией на токсоплазмоз и герпесвирусы

Herpes simplex virus (HSV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) are viruses capable of establishing latency. All of these infect the CNS and have been detected in human postmortem brains. Toxoplasma gondii is a protozoan organism which can reactivate in the brains of previously infected immunocompromised individuals. To screen for the presence of herpesviruses and T. gondii in postmortem orbital frontal brain samples from patients with schizophrenia, affective disorders, and controls, we used nested-polymerase chain reaction (n-PCR)/sequencing. We identified HHV-6B sequences in 2/51 postmortem brain samples but no sequences from other herpesviruses. We did not detect sequences of T. gondii in the postmortem brains. Additional studies including ones directed at the sensitive detection of viral nucleic acids in multiple brain regions should be directed at confirming or excluding a role for viruses and protozoa in the etiology of these disorders.

Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients

+ Antibodies to Toxoplasma gondii in Patients With Schizophrenia: A Meta-Analysis
+ Toxoplasmosis–Schizophrenia Research

Бупренорфин в терапии резистентной депрессии

Nonetheless, there has been little work published concerning the antidepressant effects of buprenorphine in treatment refractory depression in the absence of opiate dependence since my 1995 paper. I find only one report, by Nyhuis et al in 2008, looking at low-dose sublingual buprenorphine monotherapy in 6 extremely treatment refractory hospitalized patients with a very marked response to a maximum dose of 0.8 to 2.0 mg/d for a total of 7 days of open label treatment. All but one of these subjects experienced full remission acutely.

Q&A: Buprenorphine for Treatment Resistant Depression?

Сравнение атипичных антипсихотиков

For example, when switching from a tightly binding anticholinergic or antihistaminergic medication (eg, olanzapine, quetiapine, clozapine) to one with less anticholinergic or antihistaminergic affinity (eg, aripiprazole, risperidone, ziprasidone), often transient rebound anxiety, insomnia, agitation and restlessness can occur. In addition, when switching from a tighter D2 binding agent to a looser-binding agent (eg, from risperidone to clozapine or quetiapine) or, particularly, to a partial dopamine agonist (eg aripiprazole) dopamine rebound symptoms, such as often transient worsening of psychosis, mania or aggression/agitation, can occur. A pharmacokinetic dopamine rebound may also occur when switching from a short half-life antipsychotic to a longer half-life antipsychotic (Table 1).4

The abrupt switch has the greatest potential for rebound and withdrawal phenomena. Even the conventional cross-titration can lead to problems when the pre-switch antipsychotic has a shorter half life and/or blocks more tightly cholinergic, histaminergic or dopaminergic receptors than the post-switch antipsychotic. Rebound phenomena can be minimized by avoiding abrupt or fast switching when the pre- and post-switch receptor affinities and/or half-lives differ considerably. Instead, an overlapping or “plateau” switch should be used. This consists of decreasing the pre-switch antipsychotic slowly (eg, 25–50% every 5 half-lives) and only after the post-switch antipsychotic has reached steady state (ie, ≤5 half lives on target dose). Adding calming medications during the switch period, such as benzodiazepines, antihistamines or sleep aides, can also minimize rebound phenomena.

A number of non-antipsychotic augmentation strategies have also been tested in schizophrenia patients with insufficient response to antipsychotic monotherapy. Of these, lithium,16 carbamazepine,17 and beta blockers18 were not superior to placebo when added to an antipsychotic. Similarly, benzodiazepine19 and valproate augmentation20 also did not show long-term superiority compared to placebo, although both agents might speed up the initial response. Although two large-scale studies showed no superiority of lamotrigine augmentation of antipsychotics compared to placebo,21 a meta-analysis demonstrated significant superiority regarding global ratings of psychopathology, positive and negative symptom change, as well as study-defined response when outcomes of patients were combined in whom lamotrigine was added to clozapine.22 This, however, has not been verified in a prospective study.

ECT augmentation has also been shown to be superior, both for acute efficacy and in maintenance treatment, when added to antipsychotic monotherapy in patients who have failed antipsychotic monotherapy.23

One meta-analysis suggested that augmentation of antipsychotics with antidepressants may be more helpful than placebo for schizophrenia patients with predominantly negative symptoms.24 Larger, validating studies are needed, however, and specific effects on negative symptoms need to be distinguished from proven effects of antidepressants on depressive symptoms in schizophrenia patients.25

Practical Dosing Strategies in the Treatment of Schizophrenia: Part 2 - Switching and Combining Antipsychotics

Монотерапия рисперидоном в сравнении с терапией комбинацией низких доз рисперидона и галоперидола

Monotherapy is recommended for schizophrenia treatment, but the risk-benefit issue of antipsychotic drug combination (except for clozapine) remains unclear. Risperidone, an atypical antipsychotic drug, has a lower incidence of extrapyramidal syndrome but higher risks of prolactinemia and metabolic syndrome than haloperidol, a typical agent. This study compared efficacy and safety of risperidone monotherapy versus low-dose risperidone plus low-dose haloperidol in schizophrenia. In this 6-week, double-blind study, patients were randomized to the combination group (2-mg/d risperidone plus 2-mg/d haloperidol, n = 46) or the monotherapy group (4-mg/d risperidone, n = 42). Efficacy assessments included Clinical Global Impression-Severity, Positive and Negative Syndrome Scale and subscales, Calgary Depression Scale, Global Assessment of Functioning, and Medical Outcomes Study Short-Form 36. Safety was rigorously monitored. Response was defined as 30% reduction in the Positive and Negative Syndrome Scale total score. The 2 treatment groups were similar in (1) demographic and clinical characteristics at baseline, (2) response rate, and (3) improvement in various psychopathological measures and quality of life at end point. The monotherapy group had a higher increase in prolactin levels (P = 0.04) and Simpson-Angus Scale scores (P = 0.04) and a higher percentage of biperiden use (P = 0.045). There were no significant between-group difference in changes in weight, vital signs, corrected QT interval, liver/renal function, fasting glucose level, and lipid profiles. The findings suggest that risperidone monotherapy may yield higher prolactin levels than a combination of low-dose risperidone plus low-dose haloperidol. The 2 treatment groups are similar in efficacy, life quality, and other safety profiles. Future long-term studies are warranted.

A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia.

Потенциирование клозапина: сульпирид, амисульприд, ламотриджин

A frequent treatment strategy for clozapine-resistant patients with schizophrenia is the use of specific augmentors that are suitable for adjunctive therapy. Clozapine is a polyvalent drug but it lacks high-potency dopamine receptor blockade (Kerwin & Osborne, 2000). Therefore, there has been interest in using as augmentors substituted benzamides with highly selective dopamine receptor blocking profiles (Kerwin, 2000). Augmentation strategies incorporating sulpiride are well documented. The authors of one study of sulpiride augmentation in 28 patients partially responsive to clozapine (Shiloh et al, 1997) noted a mean reduction of about 40–50% in various clinical response scores (Brief Psychiatric Rating Scale and Scale for the Assessment of Positive Symptoms).

Several groups have been interested in mimicking this study with amisulpride, a relative of sulpiride that is even more selective at the dopamine D2 receptor. A case series by Zink et al(2004) showed improvement in previously treatment-resistant symptoms following a combined treatment strategy of clozapine and amisulpride. In addition, our group performed an open trial of amisulpride augmentation in a long-term (52 weeks) study. Significant improvement was observed in half of the patients, with no additional side-effects. Moreover, this study monitored plasma levels to determine whether this was a pharmacokinetic interaction. Clozapine levels did not change throughout the duration of the trial, suggesting a pharmacodynamic interaction (Munro et al, 2004).

Augmentation with anti-epileptics
A glutamate hyperfunction hypothesis of schizophrenia has generated interest in the role of glutamate release inhibitors as clozapine augmentors. In a study of 26 treatment-resistant patients receiving lamotrigine (17) or topirimate (9) in addition to their existing antipsychotic treatment (a variety of antipsychotics), a significant improvement was observed when lamotrigine was added to risperidone, haloperidol, olanzapine or flupenthixol. However, no significant effect was observed in patients receiving topirimate augmentation in addition to clozapine, olanzapine, haloperidol or flupenthixol (Dursun & Deakin, 2001). The therapeutic effects of lamotrigine augmentation were also assessed in a rigorous randomised placebo-controlled cross-over study of 34 clozapine-resistant patients (Tiihonen et al, 2003). In this 14-week study, lamotrigine treatment significantly improved positive symptoms and general psychopathological symptoms, but had no effect on negative symptoms. The authors suggested that this was the first time a non-dopamine antagonist had proven efficacy in schizophrenia, giving further credence to the hyperglutamate neurotransmission hypothesis for the generation of positive symptoms in the disorder.

Management of clozapine-resistant schizophrenia

Аутистическая симптоматика в результате вирусного поражения головного мозга

What happened to her? She suffered from herpes simplex encephalitis, a viral infection of the brain. X-rays at the age of 22 showed serious damage to the temporal lobes of the brain, extending to parts of the parietal lobes. (No pictures were provided, however.)

Can her case really be described as a "typical autistic syndrome"? Certainly, there are striking similarities, from the obsessive routines, to the echolalia (repeating what other people say), to the avoidance of eye contact, all classic symptoms of severe autism.

Of course it's always possible that the case report was written to accentuate these similarities, in order to make a nice publication. There have been a handful of other similar cases, though the same caveats apply. Still, if we do accept that these patients are indeed autistic, the implications for understanding the neurobiology of "normal" autism are obvious.

Autism Following Viral Infection

Баклофен при абстинентном синдроме

A small study in Minnesota has replicated findings from Italy indicating that off-label use of the gamma-aminobutyric acid–derivative baclofen is effective in treating symptoms of alcohol withdrawal syndrome (AWS). The drug has been approved for treating spasticity.

The prospective, double-blind, randomized, placebo-controlled study involved 79 inpatients at risk for AWS. Of these, 44 developed symptoms of AWS and were randomly assigned to receive baclofen 10 mg or placebo 3 times per day. In all, 31 patients completed the 72 hours of observation and assessment required by the study and were available for evaluation.

When the study was unblinded, the researchers found that 1/18 patients in the baclofen group and 7/13 patients in the placebo group (P = .004) required a high dose of benzodiazepines (20 mg or more of lorazepam) during the 72-hour period to control symptoms of AWS.

Baclofen Can Ease Symptoms of Acute Alcohol Withdrawal

Ингибиторы холинэстеразы при делирии

Use of the cholinesterase inhibitor rivastigmine (Exelon; Novartis) does not decrease the duration of delirium in critically ill patients in intensive care units (ICUs) when added to standard treatment with haloperidol, and might increase the risk for death, according to results of a large, placebo-controlled trial published online November 5 in The Lancet.

No Benefit, Possible Harm With Cholinesterase Inhibitor for Delirium

Эффективность приёма антипсихотика через день

Objective: In the treatment of schizophrenia, all currently available oral antipsychotics are administered at least once daily, with strict adherence strongly encouraged to minimize risk of relapse. Based on a better understanding of the brain kinetics of antipsychotics, we have proposed a variation of this approach, “extended” dosing, which allows for intermittent but regular dosing.

Method: We carried out a randomized, double-blind, placebo-controlled trial evaluating 35 individuals with DSM-IV–defined schizophrenia who had been stabilized on antipsychotic therapy. Over a 6-month interval, 18 subjects received their medication as usual (daily), while 17 received their antipsychotic therapy every second day (extended). Outcome measures included clinical scales to assess symptoms (Brief Psychiatric Rating Scale [the primary outcome measure], Calgary Depression Scale), illness severity (Clinical Global Impressions-Severity of Illness scale), and relapse (ie, rehospitalization) rates. Side effects were also assessed, including movement disorders (Barnes Akathisia Scale, Simpson-Angus Scale, Abnormal Involuntary Movement Scale) and weight. The study was conducted from February 2003 to July 2007.

Results: Individuals in the extended dosing group were not at greater risk of symptom exacerbation, relapse, or rehospitalization; indeed, more rehospitalizations occurred in those receiving regular dosing. At the same time, though, there was no indication that side effects were significantly reduced in the extended dosing group.

Conclusions: These results challenge the long-standing dogma that oral antipsychotics must be administered daily in stabilized patients with schizophrenia. Further studies with larger samples are needed to replicate these findings, as well as to elucidate whether postulated clinical advantages can be established and determined to outweigh potential risks.

“Extended” Antipsychotic Dosing in the Maintenance Treatment of Schizophrenia: A Double-Blind, Placebo-Controlled Trial

Окситоцин и негативная симптоматика шизофрении

Oxytocin is a hormone that has been reported to reduce the severity of schizophrenia when administered intra-nasally. Rubin and colleagues from the University of Illinois at Chicago report that women with schizophrenia showed less severe symptoms on the Positive and Negative Syndrome Scale (PANSS) in the mid-luteal phase compared with the follicular phase. Higher oxytocin levels in both men and women were associated with more prosocial behaviors. This lends credence to the potential usefulness of oxytocin in schizophrenia, which also is being studied in autism. As a researcher, I also think this study points to the possibility that PANSS ratings in clinical trials of antipsychotics should control for the menstrual phase to avoid the confounding effects of a decline in severity of psychosis during the mid-luteal phase irrespective of drug treatment.

Oxytocin is a hormone that has been reported to reduce the severity of schizophrenia when administered intra-nasally. Rubin and colleagues from the University of Illinois at Chicago report that women with schizophrenia showed less severe symptoms on the Positive and Negative Syndrome Scale (PANSS) in the mid-luteal phase compared with the follicular phase. Higher oxytocin levels in both men and women were associated with more prosocial behaviors. This lends credence to the potential usefulness of oxytocin in schizophrenia, which also is being studied in autism. As a researcher, I also think this study points to the possibility that PANSS ratings in clinical trials of antipsychotics should control for the menstrual phase to avoid the confounding effects of a decline in severity of psychosis during the mid-luteal phase irrespective of drug treatment.

Peripheral oxytocin is associated with reduced symptom severity in schizophrenia

Влияние гипертензии и индекса массы тела на когнитивные функции больных шизофренией

Objective: In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects.

Method: The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2x2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects).

Results: Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance.

Conclusions: Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.

The Effects of Hypertension and Body Mass Index on Cognition in Schizophrenia

Виагра, когнитивные функции, негативная симптоматика шизофрении

We know that sildenafil (Viagra) helps restore erectile functioning, but not many people know that it also has cognitive-enhancing and neuroprotective effects in rodents. A double-blind, placebo-controlled study from Iran by Akhondzadeh et al suggests that sildenafil can significantly improve negative symptoms of schizophrenia. The study may lead to an important adjunctive use of this drug if it is replicated with a larger sample. The putative mechanism is the inhibition of phosphodiesterase 5 (PDE5), resulting in increased cyclic guanosine monophosphate (cGMP), which may correct the hypofunctioning N-methyl-D-aspartic acid (NMDA) glutamate receptor believed to be associated with elevated dopamine in the mesolimbic tract (causing positive symptoms) and a decline in dopamine in the mesocortical tract (causing cognitive deficits and negative symptoms).

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial

Свекла, нитраты и мозг

Drinking beet juice increases blood flow to the brain in older people, a finding that suggests the dark red vegetable may fight the progression of dementia, a new study shows.

Beet roots contain high concentrations of nitrates, which are converted into nitrites by bacteria in the mouth. And nitrites help open blood vessels in the body, increasing blood flow and oxygen to places lacking in oxygen.

Previous studies have shown that nitrites -- also found in high concentrations in celery, cabbage, and other leafy, green vegetables like spinach -- widen blood vessels, but researchers say this was the first to find that nitrites also increase blood flow to the brain.

Beet Juice Good for Brain

Терапия генерализованного тревожного расстройства

Studies comparing antidepressants with benzodiazepines in the treatment of GAD showed that although benzodiazepines work quickly, the antidepressants lower anxiety more effectively in the long term.[11] Antidepressants that have been approved by the United States Food and Drug Administration (FDA) for the treatment of GAD are extended-release venlafaxine,[12] duloxetine,[13] escitalopram,[14] and paroxetine.[15] Although not FDA approved, citalopram has also been found to be effective for the treatment of GAD.[16] Whereas benzodiazepines have been shown effective for shortterm anxiety, they may worsen depression, a common comorbidity of GAD, and cause other cognitive adverse effects such as sedation and anterograde amnesia. Individuals with a history of substance abuse or dependence should not use benzodiazepines, but patients with no such history rarely abuse these agents and can use them safely.[17] Buspirone and pregabalin also have proven efficacy for GAD.[18–21]

Table 1. Summary of Clinical Trials of Adjunctive Use of Atypical Antipsychotics for Treatment-Resistant Generalized Anxiety Disorder^a

Agent	Study Design	No. of Patients	Study Duration (wks)	Mean Daily Dose (mg)	Change in Assessment Score	Mean Weight Gain (lbs)b
Aripiprazole[30]	Open label	17	4.9	16.9	CGI-S: −1.6	NR
Aripiprazole[31]	Open label	10	9	NR	HAM-A: −20.6	7.1
Aripiprazole[32]	Open label	9	6	13.9	HAM-A: −12 CGI-I: 8 of 9 patients rated as much improved or very much improved	NR
Aripiprazole[33]	Open label	23	8	10.5	HAM-A: −6.7 CGI-S: −1	2.5
Olanzapine[34]	Randomized, controlled	21	6	8.7	HAM-A: olanzapine −7 vs placebo −3.9 (p=0.4) CGI-S: 67% of patients rated as not at all ill or borderline ill	11
Quetiapine[35]	Randomized, controlled	58	8	182	HAM-A: quetiapine −12.5 vs placebo −5.9 (p=0.002)	5.2
Quetiapine[36]	Randomized, controlled	22	8	120	HAM-A: quetiapine −2.6 vs placebo −0.3 (p=0.98)	2.7
Quetiapine[37]	Open label	40	12	386	HAM-A: −20.6	1.1
Risperidone[38]	Open label	16	8	1.12	HAM-A: −6.75 CGI-S: −1.53	3.9
Risperidone[39]	Randomized, controlled	40	5	1.1	HAM-A: risperidone −9.8 vs placebo −6.2 (p=0.034)	2.3
Risperidone[40]	Randomized, controlled	390	4	0.86	HAM-A: risperidone −9.26 vs placebo −9.12 (p=0.858) PaRTS-A: risperidone −8.54 vs placebo −7.61 (p=0.265)	2.65
Ziprasidone[41]	Open label	13	7	40	HAM-A: −11.2	0.2

HAM-A = Hamilton Rating Scale for Anxiety (lower scores indicate less severe symptoms of anxiety); CGI-S = Clinical Global Impressions-Severity (lower scores indicate less severe illness); CGI-I = Clinical Global Impression–Improvement; NR = not reported; PaRTS-A = Patient-Rated TroublingSymptoms for Anxiety.
^aAll atypical antipsychotic treatment was added to current antidepressant therapy.
^bIn patients who received the atypical antipsychotic.

Adjunctive Use of Atypical Antipsychotics for Treatment-resistant Generalized Anxiety Disorder

Атеросклероз и депрессия

Atherosclerosis does not appear to increase the risk for incident depression in older adults — a finding that runs contrary to the so-called vascular depression hypothesis, which asserts that vascular factors precede the onset of depression in this patient population.

No Link Between Atherosclerosis and Increased Depression Risk

Средство от эмоциональной лабильности при органических поражениях головного мозга

The US Food and Drug Administration (FDA) has approved dextromethorphan HBr and quinidine sulfate 20 mg/10 mg capsules (Nuedexta; Avanir Pharmaceuticals, Inc) as the first treatment for pseudobulbar affect (PBA).

PBA occurs secondary to brain injury or neurologic conditions such as multiple sclerosis, amyotrophic lateral sclerosis (ALS), and stroke. Also known as emotional incontinence, it is characterized by sudden outbursts of involuntary crying and/or laughing that can cause anxiety and embarrassment in public settings.

FDA Approves First Treatment for Pseudobulbar Affect

Шизофреноподобный психоз при болезни Альцгеймера с ранним началом

Our patient was a 65-year-old right-handed woman. In August 2003, her family noticed her mild memory disturbance, and she developed delusions that someone intruded into her house, always watched her, and stole her bankbook. In March 2005, she developed auditory hallucinations that someone told her bad things. She also insisted that someone let snakes loose in her house and that someone hid himself under the stool and watched her. She was first diagnosed with schizophrenia and prescribed risperidone. At the next visit, the Mini-Mental Status Examination was administered and she scored 21/30. MRI showed mild diffuse brain atrophy, and SPECT showed right-dominant decreased rCBF in the temporoparietal lobe. Considering these results, her diagnosis was changed to early-onset Alzheimer’s disease. Donepezil was prescribed, and her psychoses were improved.

Schizophrenia-Like Psychosis and Dysfunction of the Right-Dominant Temporoparietal Lobe in Early-Onset Alzheimer’s Disease

Кетамин и депрессия

Their article describes robust, clinically relevant, and rapid alleviation of depression symptoms in patients with bipolar disorder that persists far beyond the presence of the drug in the body. Ketamine has a terminal half-life of approximately 3 hours. Yet after 2 days, or 16 half-lives, of ketamine, the effect size of its antidepressant effects was large (0.8). Impressively, at 2 weeks there were still traces of the antidepressant effects of single ketamine dose, associated with an effect size of 0.22.

N- methyl-D-aspartate Glutamate Receptor Antagonists and the Promise of Rapid-Acting Antidepressants

Аффективные расстройства быстрого цикла ассоциированные с менструальным циклом

Affective fluctuations during menstruation have drawn considerable interest from researchers for a long time.1 Data indicates increased frequency of depression associated with menstrual period in adolescence,2 though there is limited information about the differences in the course or symptoms of bipolar disorder associated with menstrual period in adolescents. The question of the direction of mood shifts in the course of bipolar disorder with specific phases of menstrual cycle has been raised, albeit with limited and inconsistent results.3 We present a case of an adolescent female with cyclic affective changes akin to rapid cycling bipolar disorder starting in the premenstrual (luteal) period and subsiding with onset of menstruation, and we try to explore the biological underpinnings of inherent propensity for the development of bipolar disorder using quantitative electroencephalography (qEEG)

There was high spectral power in low frequency (theta band) over the right temporal region which was further corroborated by LORETA and revealed high signal density over the right temporal region for the same frequency band

A review3 presented findings of 24 prospective studies of affective fluctuations during the menstrual cycle. In most cases the authors found that negative moods marked by irritability, restlessness, anxiety, tension, migraine, sleep disturbance, and impaired concentration occurred more often during the premenstrual and menstrual phases than at other times in the cycle. There were only a few cases of positive moods—such as an increased feeling of well-being, elation, pleasantness, and activation—during the follicular and midcycle phases.3 This case presents with positive mood state, though irritability and headache were present as seen in premenstrual syndrome (PMS). This is an atypical presentation of PMS as opposed to the more common occurrence of elated moods during midcycle; in our case it occurred in premenstrual phase.7 It has been reported that whereas menstrual problems appear to occur more frequently in younger than in older women, premenstrual symptoms occur more often in older women. This suggests a relation between age and menstrual symptoms.

The overlap in symptomatology between PMS and cyclothymia, often considered to be a variant of manic-depressive illness, has given rise to therapeutic trials of lithium carbonate in women with PMS, with mixed results.14 Lithium treatment has been beneficial in controlling premenstrual affective changes, and this led us to use the same in our case.

Rapid Cycling Associated With Menstrual Periods in an Adolescent: Electrophysiological Underpinnings for Bipolarity

Натуральные источники серотонина, мелатонина и триптофана

There are some high-content sources of serotonin, melatonin, and tryptophan which can provide the body with these substances. These include plantains, pineapples, bananas, kiwis, plums, and tomatoes for serotonin; white and black mustard, wolfberry seeds, and fenugreek seeds for melatonin; and cottage cheese, soy protein, peanuts, beans, wheat flour, and potatoes for tryptophan

Depression and Fruit Treatment

Нейротоксичность лития при нормальных концентрациях

To the Editor: Lithium is used with great success in the treatment and prophylaxis of bipolar disorders, unipolar recurrent depression, and endogenous depression that is resistant to conventional treatment. It is also known to be neurotoxic at higher serum levels. In rare cases patients develop symptoms of intoxication even with normal lithium levels.

Case Report

A 61-year-old man with history of bipolar disorder that was managed with lithium for more than 20 years presented with complaints of psychomotor slowdown, unsteady gait, memory deficits, restlessness, sleep disorder, and severe tremor in his hand that prevented him from eating or drinking properly. These symptoms had begun in the previous week. There was no recent history of fever, respiratory, gastrointestinal, or urinary complaints. He was medicated with lithium, 800 mg/day, and fluvoxamine, 200 mg/day, and the dosage of his medication had remained unchanged over the last year.

Neurological examination showed psychomotor slowdown, inattention, temporal disorientation, severe episodic memory impairment, motor and verbal perseveration, slurred speech, and hypophonia. Symmetrical global and segmental bradykinesia and lead-pipe rigidity, as well as tremor at rest, intention, and posture, were also evident. His gait was abnormal with shuffling small steps and a hunched-forward upper body.

An analytic study revealed no abnormalities, including CBC, renal, thyroid and hepatic function, and PCR. Lithium serum levels were normal (1.0 mmol/liter).

EEG showed diffuse slow background activity, mainly at 5–6 Hz, with periods of greater lentification at 3 Hz, which is compatible with moderate to severe encephalopathy. A brain CT was normal. The patient was admitted and lithium was stopped. There was remarkable clinical improvement over the next days, and he was discharged at day 5, asymptomatic and on valproic acid (300 mg/day).

Lithium Neurotoxicity at Normal Serum Levels

Дисфагия при приёме палиперидона

Paliperidone-Induced Dystonic Dysphagia

Глутаматергические механизмы ОКР

Glutamatergic Dysfunction in Obsessive-Compulsive Disorder and the Potential Clinical Utility of Glutamate-Modulating Agents

Альтернативные методы лечения шизофрении

Outside of India, however, Sen and Bose's observations on the use of rauwolfia for psychotic disorders were generally ignored. It was not until 1954, when Nathan Kline2 reported that both whole root rauwolfia extract and reserpine—a purer preparation—seemed to be somewhat more effective than placebo in more than 400 inpatients with neuropsychiatric conditions, that clinicians in the West took notice. Although it soon became apparent that phenothiazines were generally more tolerable than reserpine, and even after our enthusiastic embrace of clozapine, a respected 1991 review3 still listed reserpine as 1 of 8 reasonable, evidence-based treatment options for persons affected with the refractory symptoms of schizophrenia.

Two essential omega-3 fatty acids were compared in a 3-month, double-blind pilot study that found that augmentation with eicosapentaenoic acid (EPA) was superior to docosahexaenoic acid (DHA) or placebo in significantly reducing Positive and Negative Syndrome Scale (PANSS) scores; a second study using EPA suggested that supplementation with omega-3 for extended periods can benefit some patients even without antipsychotics.

On the other hand, a 16-week trial in 87 patients that compared 3 g/d of e-EPA with placebo found no difference in positive, negative, mood, or cognitive symptoms of schizophrenia.26 Noting that both the active and placebo groups had improvements in their PANSS ratings, these investigators evaluated the placebo response in 37 study participants and found that the 9.5% improvement in the PANSS total score usually occurred by the end of the first 2 weeks of participation, which argues for the value of a placebo run-in phase for future studies.27

Revisiting the initial findings of plasma membrane abnormalities, a 24-hour dietary recall in 146 community-dwelling patients with schizophrenia found little difference in dietary fatty acid and antioxidant intake from controls.28 However, a more elaborate evaluation of 72 subjects with schizophrenia found that the previously reported membrane lipid abnormalities could be explained by the fact that many of the subjects were smokers and had a significantly different omega-3 dietary intake from that of the controls.

Sitting between mainstream and alternative therapies are amino acid treatments, derived from the recognition that phencyclidine (PCP) psychosis was a better model for schizophrenia than the previous model of amphetamine psychosis. Among other observations, those with PCP intoxication presented with negative as well as positive symptoms. The mechanism of PCP's action was eventually elucidated; it specifically blocked the ion channel in NMDA (N-methyl-d-aspartate) glutamate receptors in the brain. An allosteric modulatory site on this complex receptor has been referred to as the "glycine" site, and its endogenous ligands plausibly may be the amino acids glycine, d-serine, and d-alanine (the latter 2 unusual d-forms present in the brain because of a racemizing enzyme).

A meta-analysis of short-term clinical trials found that treatment augmented with the agonists glycine and d-serine moderately reduced negative symptoms, while partial agonist d-cycloserine was less efficacious.35 These agents do not appear helpful for patients treated with clozapine, although glycine and d-serine may be effective for those being treated with olanzapine or risperidone.

High homocysteine levels have been found to interfere with NMDA receptors in animal studies. Neeman and coauthors46 reported finding lower plasma glycine levels and higher homocysteine levels in patients with schizophrenia compared with controls, and glycine levels correlated with increased negative symptoms. Findings of higher homocysteine levels in patients with schizophrenia may often involve folate-deficient dietary choices, obesity, or cigarette smoking, but one study found that these variables explained relatively little of the high homocysteine levels

Oxidative stress/free radical damage has been proposed as mediating pathology in various neuropsychiatric disorders, including schizophrenia. Small initial trials failed to shed adequate light on the value of ascorbic acid (vitamin C) in the treatment of schizophrenia,49,50 although a recent 8-week study reported significant improvement in Brief Psychiatric Rating Scale scores for those receiving an adjunctive 500 mg/d dosage of vitamin C.51 In addition, one study25 with positive findings used adjunctive omega-3 with vitamins C and E. Additional studies are needed to evaluate this approach.

Another putative adjunctive antioxidant strategy in schizophrenia involves the addition of EGb, a standardized Ginkgo biloba extract. Although several studies have shown fairly consistent preliminary results,52-54 larger and more definitive studies are still needed.

The higher rates of schizophrenia in those born in winter or spring, and the reported association between prenatal exposure to the 1945 famine of the "Dutch Hunger Winter" and later development of schizophrenia in offspring may be rationalized by the hypothesis that schizophrenia is more prevalent in those who have had vitamin D deficiency during the first year of life. The results of a 1966 study of a Finnish-birth cohort lend support to this theory.63 However, as there were very few children not given the then-recommended vitamin D supplement, and since not receiving the supplement may have been associated with other plausible risk factors, this single study provides only weak support for this interesting idea.

Treatment Resistance in Schizophrenia: The Role of Alternative Therapies