Потенциальные механизмы лечения депрессии

EMERGING THERAPEUTIC TARGETS


Consider the following novel mechanisms that may become the basis for creating entirely new antidepressants in the foreseeable future, by design, not by serendipity:

• corticotropin-releasing factor (CRF) and glucocorticoids

         – CRF antagonists
           – vasopressin receptor antagonists
           – glucocorticoids as agonists or antagonists

• neurokinin system
• brain derived neurotropic factor (BDNF) and other neurotropins, such as fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF)
• phosphodiesterase inhibitors
• glutamate pathway modulators

        – ketamine (IV infusion with immediate efficacy)
          – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor modulators
          – glycine

• hypothalamic feeding peptides
• circadian gene products
• other evolving antidepressants

        – K-opioid receptor antagonists
          – CB1 cannabinoid receptor agonists/antagonists
          – cytokines
          – melatonin receptor agonists
          – galanin
          – neuropeptide Y
          – histone deacetylase inhibitors
          – tissue plasminogen activator

 The hazards of serendipity

Глутаматергические лекарственные средства для лечения шизофрении

Glutamatergic drugs in development

Target	Proposed mechanism	Proposed agents	Phase of development
Glycine/D-serine receptor	Allosteric modulator of the NMDA receptor	Glycine, D-serine, D-alanine, D-cycloserine	Phase II
Glycine-type I transport inhibitor	Blocks the reuptake of glycine, akin to SSRIs’ action on serotonin	Sarcosine, RG1678	Phase II/III
Metabotropic glutamate type 2/3 (mGluR2/3)	Blocks presynaptic glutamate release	LY-2140023	Phase II
Redox sensitive site	Allosteric modulator of the NMDA receptor	N-acetylcysteine	Phase II
D-amino acid oxidase (DAAO) inhibitors	Inhibits the enzyme that metabolizes D-serine	Remains in preclinical stage
Tetrahydrobiopterin (BH4)	Indirectly modulates glutamatergic system	Remains in preclinical stage
NMDA: N-methyl-D-aspartate; SSRIs: selective serotonin reuptake inhibitors

Glycine/D-serine site agonists. To date, most studies have used glutamatergic drugs adjunctive to antipsychotics and targeted the glycine/D-serine modulatory site, in part because glycine and D-serine are natural compounds and therefore FDA approval for their use could be obtained without the extensive preclinical development usually required for new chemical entities.¹⁶ Unfortunately, these agents are less potent than traditional pharmaceuticals, and delivering optimal doses may be impossible. Nevertheless, positive studies with these compounds have provided proof-of-concept for development of agents with higher affinity and specificity.

Studies have used glycine administered at doses up to 60 g/d, D-serine up to 8 g/d, or D-alanine approximately 6 g/d. For glycine, 60 g/d is the highest dose that can be given because of concerns about tolerability and replacement of other essential amino acids. D-serine originally was tested at approximately 2 g/d with promising results, but a recent open-label trial suggested that higher doses may be more efficacious.¹⁷ D-serine doses are limited by potential renal toxicity, as demonstrated in rodents studies.

Although not all studies of glycine/D-serine site agonists have been positive, a recent meta-analysis suggests significant improvement in negative symptoms across studies.¹⁸ Variability in statistical results across studies is related primarily to degree of placebo effect within individual trials, with a mean improvement in negative symptoms of approximately 15%. Glycine/D-serine site agonists seem to be less effective when combined with clozapine, possibly because clozapine may already enhance the glutamatergic system and increase synaptic glycine levels.⁶

One study that evaluated effects of open-label glycine in individuals with schizophrenia symptoms observed a large effect-size improvement, including early remission in 3 of 10 patients.¹⁹ These data—if confirmed by double-blind trials—would indicate that glycine/d-serine site agonists might have utility in treating the schizophrenia prodrome.

Glycine transport inhibitors. A potential indirect approach to raising glycine levels in the brain is using GlyT1-type glycine transport inhibitors (GTIs). GlyT1 transporters are co-localized in brain with NMDARs and modulate local glycine levels. Rather than binding directly to the NMDAR glycine binding site, GTIs increase glycine levels in the synapse by preventing its removal by GlyT1 transporters. Their function is analogous to using selective serotonin reuptake inhibitors to increase serotonin levels in patients with depression.⁶

Sarcosine (N-methylglycine) is a naturally occurring GlyT1 inhibitor that has been used in early clinical trials in Taiwan. Initial studies with sarcosine showed efficacy similar to—and in some cases better than—that of direct glycine/D-serine site agonists when added to first-generation or non-clozapine second-generation antipsychotics.¹⁸ Sarcosine also has been found to be effective for acute treatment of schizophrenia.²⁰ At present, however, sarcosine is not available for experimental use in the United States because of toxicity considerations.

Using high-affinity GTIs for schizophrenia was first proposed in the mid-1990s,⁶ but such compounds are only now entering clinical efficacy studies. Most recently, phase II results were presented for RG1678, a compound developed by Hoffman LaRoche.²¹ The study targeted persistent negative symptoms in patients receiving chronic antipsychotic treatment. Adding RG1678, 10 mg and 30 mg, to antipsychotics led to significant improvement in persistent negative symptoms vs placebo. These promising results are being followed up in phase III studies.

Other glutamatergic options. Few compounds are available to modulate NMDARs at sites other than the glycine/D-serine site. One study administered N-acetylcysteine, a glutathione precursor, as a potential treatment for persistent negative symptoms.²² Encouraging clinical results were observed in this double-blind study, along with improvement in electrophysiologic measures, negative symptoms, and overall functioning, but the study was limited by relatively high rates of noncompletion. Preclinical studies have combined D-serine with an inhibitor of D-amino acid oxidase to prevent D-serine breakdown.²³ In rodents, this approach produces a 30-fold increase in D-serine potency.

Tetrahydrobiopterin (BH₄) is a cofactor for enzymes responsible for the synthesis of dopamine and other monoamines, and presynaptic release of dopamine and glutamate. Reductions in BH₄ levels have been reported in schizophrenia, which suggests that this compound may be etiologically important.²⁴ Researchers have initiated a study of this compound in schizophrenia.

Other schizophrenia models propose that the crucial issue is not NMDA blockade but subsequent dysregulation of presynaptic glutamate release. Type 2/3 metabotropic glutamate receptors (mGluR2/3) are located on presynaptic glutamate terminals and inhibit presynaptic glutamate release. mGluR2/3 agonists have been shown to reverse ketamine’s effects in humans and in animal models,^25,26 which suggests a potential role in schizophrenia treatment.

The first mGluR2/3 agonist entered into monotherapy clinical efficacy trials for schizophrenia was LY-2140023. In an initial trial, this compound showed significant efficacy in improving positive and negative symptoms, comparable to that of olanzapine.²⁷ However, a follow-up study failed because of a large placebo effect,²⁸ which leaves the efficacy question unresolved.In contrast to mGluR2/3, type 5 metabotropic receptors (mGluR5) are co-localized with NMDA receptors and potentiate activation. Thus, mGluR5 agonists also may be effective for treating schizophrenia. These compounds remain in preclinical development. Other approaches, such as stimulating specific types of GABA receptors to overcome glutamatergic deficits, remain promising but have not been tested in definitive clinical trials.
Glutamate: New hope for schizophrenia treatment

Фолаты могут ослаблять негативную симптоматику у некоторых больных шизофренией

Folate supplementation appears to improve negative symptoms in schizophrenia patients, but only among those with a genetic variant of a folate-metabolizing enzyme, study results show.

It follows an earlier study by the same group showing that schizophrenia patients with low serum folate levels who were also homozygous for the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene had severe negative symptoms.

Folate may improve negative symptoms in some schizophrenia patients

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

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