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