Перспективные стратегии лечения когнитивной симптоматики шизофрении

A randomized, double-blind, placebo-controlled study demonstrated that members of a sarcosine (2 g/day) group showed greater reductions in their Positive and Negative Syndrome Scale (PANSS) total scores than members of a placebo group or D-serine (2 g/day) group, suggesting that sarcosine is superior to D-serine in that benefits both patients with long-term stable disease and also acutely ill persons with schizophrenia .

Furthermore, a randomized, double-blind study reported that sarcosine (2 g/day) alone was effective in the treatment of acutely symptomatic drugfree patients with schizophrenia.

Nonetheless, all these findings suggest that GlyT-1 inhibition could be a novel pharmacotherapeutic target for enhancing cognitive dysfunction in schizophrenia and several clinical trials are underway with very promising results.

Gaining a better understanding of the role of GlyT-1 in the treatment of cognition in schizophrenia is expected to provide new perspectives for treating this disorder. The pharmacological modulation of glycine modulatory sites on NMDA receptors by GlyT-1 inhibitors could be beneficial in the treatment of the cognitive deficits and psychosis associated with schizophrenia and other psychiatric conditions.

Galantamine, which acts as both a cholinesterase inhibitor and a nicotinic receptor modulator had the best result. The cognitive effects of galantamine may be accentuated by its nicotinic allosteric agonist action, which can improve attention and memory. Furthermore, galantamine appears to more powerfully elevate frontal cortical dopamine levels than cholinesterase inhibitors such as donepezil. This biological effect may be significant since frontal dopaminergic deficits have been proposed to underlie cognitive impairment in schizophrenia.

Importantly, significant improvement in attentional set shifting was seen. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Patient with schizophrenia manifest signs of a dysregulation of the NPY system. Extensive preclinical studies suggest that the neuropeptide Y (NPY) counteracts the behavioral consequences of stress and anxiety to and maintain emotional homeostasis. Thus it is involved in stress regulation and coping.

Treatment of Cognition in Schizophrenia

Перспективы лечения БАР

Excitotoxicity
Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.6
Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).
Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine(Drug information on ketamine) combined with lithium or valproate(Drug information on valproate) was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib(Drug information on celecoxib) was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).10 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.

Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone(Drug information on rosiglitazone)) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetylcysteine (1 g bid) adjunctive to usual medications was capable of alleviating depressive symptoms as measured by the MADRS.14 The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale. N-acetylcysteine did not induce hypomania or mania and was well tolerated. Adverse events reported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heartburn, and increased joint pain.

Armodafinil is the longer-lasting isomer of modafinil, and its therapeutic indications are similar to those of the racemic agent modafinil. Armodafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who received either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.

Novel Treatment Avenues for Bipolar Depression

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

Вакцина от кокаиновой зависимости

Cocaine is a very simple molecule, but you can attach a simple molecule to a complex molecule and still trigger the immune system. You can use this method to develop antibodies to cocaine. When an individual uses cocaine, the antibodies will bind to the cocaine in the blood stream and the drug never reaches the brain because the molecule is now too large to pass the blood-brain barrier.

Pharmacotherapy for cocaine dependence: Most evidence is weak

Study	Design	Results
Disulfiram
Pani et al, 20108	Meta-analysis of 7 studies with 492 cocaine-dependent patients	Researchers found ‘low evidence’ supporting disulfiram for treating cocaine dependence
Modafinil
Dackis et al, 20059	62 cocaine-dependent patients randomized to modafinil, 400 mg/d, or placebo for 8 weeks	Patients receiving modafinil provided significantly more BE-negative urine samples and were significantly more likely to achieve ≥3 weeks of cocaine abstinence
Anderson et al, 200910	210 cocaine-dependent patients randomized to modafinil, 200 mg/d or 400 mg/d, or placebo for 12 weeks	Modafinil significantly reduced cocaine craving but did not significantly improve the average weekly percentage of cocaine non-use days
Tiagabine
Winhusen et al, 200711	141 cocaine-dependent patients randomized to tiagabine, 20 mg/d, or placebo for 12 weeks	No significant changes in cocaine use vs placebo as measured by self-report and urine BE
Baclofen
Kahn et al, 200912	Cocaine-dependent patients randomized to baclofen, 60 mg/d, or placebo for 8 weeks	No significant difference between groups in cocaine use as measured by urine BE
Ondansetron
Johnson et al, 200613	63 cocaine-dependent patients randomized to ondansetron, 0.25 mg, 1 mg, or 4 mg twice daily, or placebo for 10 weeks	The odansetron 4 mg group had a significantly greater rate of improvement in percentage of patients with a cocaine-free week compared with the placebo group
BE: benzoylecgonine

Vaccine for cocaine addiction: A promising new immunotherapy

Стимуляторы при БАР

Clinical studies of stimulant use in patients with bipolar disorder

Stimulant(s) studied	Study design	Patients studied	Clinical outcomes
Traditional stimulants
Adjunctive methylphenidate	Chart review, naturalistic	16 adults (5 with comorbid ADHD, 11 with bipolar depression)	Improvements in depression, overall functioning, and ability to concentrate; sleep disturbance, irritability/agitation reported
Adjunctive methylphenidate or racemic mixture of AMPH salts	Chart review of sedation and depressive symptoms	8 adults (BD II)	Improved clinical impression of bipolar illness; no manic switches, changes in cycling patterns, or substance abuse noted
Adjunctive methylphenidate	12-week open study, bipolar depression	12 adults (10 BD I, 2 BD II)	Significant clinical improvements in depressive symptoms; no change in manic symptoms; anxiety, agitation, and hypomania reported
Multiple stimulants	Chart review, history of stimulants and bipolar illness course	34 hospitalized adolescents	Prior stimulant treatment associated with earlier age of illness onset
Adjunctive mixed amphetamine salts	Randomized, placebo-controlled; comorbid BD and ADHD	30 children with ADHD symptoms stabilized on divalproex sodium	Decrease in ADHD symptoms with adjunctive amphetamine treatment but not with divalproex sodium alone; 1 case of mania
Novel stimulant
Adjunctive modafinil	Case series	Mixed sample of depressed adults (4 unipolar, 3 bipolar)	Significant improvement in depressive symptoms
Adjunctive modafinil	Randomized, double-blind, placebo-controlled	85 adults with bipolar depression	Treatment group showed greater response and remission of depressive symptoms compared with placebo group; no difference in development of manic symptoms
ADHD: attention-deficit/hyperactivity disorder; AMPH: amphetamine; BD: bipolar disorder; NOS: not otherwise specified

Adding a stimulant could improve residual symptoms, but it also might cause serious side effects, toxicities, and destabilization.

Stimulants for adult bipolar disorder?

Атипичные антипсихотики: сон, седация и эффективность

"In general, the high-milligram, low-potency antipsychotics, such as chlorpromazine and mesoridazine, produce more sedation than the low-milligram, high-potency antipsychotics such as haloperidol and fluphenazine (Table 1).6 This principle tends to hold true for the atypical antipsychotics as well. For example, the high-potency, low-dose atypical antipsychotic risperidone is less sedating than the lower-potency, high-dose atypical antipsychotics quetiapine and clozapine. However, dose does not always determine sedation. Olanzapine, which has a common dose range of 15 to 30 mg/day, is more sedating than ziprasidone, which has a common dose range of 80 to 160 mg/day. Studies have indicated that sedation may also be related to the affinity of the medication for the histamine H1 receptors. The antipsychotics vary in their ability to block these receptors.4,7 A study by Richelson and Souder7 of the binding profiles of antipsychotic medications found that olanzapine has the highest affinity for the histamine H1 receptors, followed by clozapine (Figure 1Figure 1.). This may explain why olanzapine has a relatively large sedative effect even though it is a high-potency medication. Of the antipsychotics studied, haloperidol had the lowest affinity for the histamine H1 receptors. Quetiapine and risperidone had the lowest affinity of the atypical antipsychotics. Although both dosage and affinity for histamine H1 receptors play a part in the sedative effect of a medication, what ultimately determines sedative effect is the amount of the drug reaching the histamine H1 receptors in the central nervous system. For example, quetiapine, which has little affinity for the histamine H1 receptors, is a less potent antipsychotic medication and requires many more milligrams to be effective than do higher-potency medications such as risperidone and ziprasidone. Because of this, quetiapine has a greater sedative effect on patients in clinical use than do risperidone and ziprasidone."

"If sedation is bothersome to patients taking antipsychotic medications, physicians can take steps to minimize it. According to the 1999 Expert Consensus Guidelines on the treatment of schizophrenia,15 physicians should consider eliminating other sedating agents from the patient's list of medications. This includes antidepressants, such as the tricyclics and mirtazapine, and mood-stabilizing medications such as valproic acid. Instructing the patient to take his or her medication at bedtime can also reduce daytime sedation. If the entire dose cannot be given at bedtime, then the majority of the dose should be taken at night. If necessary, the physician should consider reducing the dose of the antipsychotic medication, but this should be done slowly and cautiously. The physician could also consider switching the patient to a less sedating antipsychotic. Also, the physician might consider checking the patient for hypothyroidism, which can cause individuals to feel sedated. If these efforts do not work, caffeine or bupropion might help the patient feel more alert. Many patients taking antipsychotic medications drink several cups of coffee every morning to feel less sedated.
The 1999 guidelines recommended prescribing stimulants for patients who were persistently sedated, but this has become highly controversial. Generally, I do not recommend prescribing stimulants for psychotic patients because sedation can usually be controlled using other means and the physician may be held liable for the patient's actions while medicated with stimulants.
A medication that has recently emerged as an option to treat drug-induced sedation is modafinil. The treatment mechanism of modafinil is unknown, and although it is a schedule IV controlled substance, it is not a stimulant. It has been used successfully in clinical settings to combat sedation, but there is concern that it may worsen psychotic symptoms. Modafinil was reported to have exacerbated psychosis in 1 patient who was taking a dose of 200 mg 4 times daily,16 but no adverse effects were reported in 3 patients who were taking 200 mg/day along with antipsychotic medications.17"

Atypical Antipsychotics: Sleep, Sedation, and Efficacy

Резистентное к лечению биполярное расстройство

In acute mania, antidepressants should be discontinued immediately. The focus should be on using evidence-based treatments for mania. Although lithium is not recommended for mixed episodes or for patients with many previous episodes, lithium and divalproex are often used before an atypical antipsychotic because they are thought to be safer with long-term use.
The most commonly recommended nonstandard treatments for treatment-resistant mania are clozapine and ECT, which have been shown to have efficacy.A combination of clozapine and ECT has also been suggested.
Several novel treatments have been studied using an augmentation approach in combination with standard treatments for treatment-resistant mania. These include donepezil, gabapentin, topiramate, mexiletine, and intravenous magnesium sulphate. The reported efficacy in these uncontrolled reports is confounded by the continuation of the previous treatments. One exception is tamoxifen, which, like lithium and valproate, inhibits protein kinase C and was found to have antimanic efficacy superior to placebo.
However, antidepressants (other than fluoxetine in combination with olanzapine) have not been shown to be efficacious in acute bipolar depression and may be associated with switching. In particular, antidepressants with norepinephrine activity including tricyclics and serotonin-norepinephrine reuptake inhibitors may have a greater risk of inducing switching than SSRIs.
For treatment-resistant acute bipolar depression, the dopaminergic agonist pramipexole and the wakefulness-promoting agent modafinil have been shown to have efficacy greater than placebo as augmentation to standard treatments.4,26 Other pharmacotherapies have been studied in uncontrolled augmentation, including donepezil, bupropion, riluzole, gabapentin, levetiracetam, and aripiprazole. Two brain-stimulating therapies—magnetic seizure therapy and repetitive transcranial magnetic stimulation (TMS)—have been studied as well.
Other approaches include augmentation with hypermetabolic thyroid supplementation, diltiazem, aripiprazole, topiramate, gabapentin, mexiletine, levetiracetam, and chromium, as well as vagus nerve stimulation. Efficacy has also been reported for levetiracetam monotherapy and a combination of topiramate and clozapine.

Treatment-Resistant Bipolar Disorder

Эффект модафинила на познавательные функции больных шизофренией

A Review of the Effects of Modafinil on Cognition in Schizophrenia