Комбинация арипипразола с клозапином эффективнее монотерапии антипсихотиком

Certain antipsychotic polytherapies, including aripiprazole and clozapine, are associated with a lower risk of psychiatric rehospitalization in patients with schizophrenia, according to Jari Tiihonen, MD, PhD, of the Karolinska Institute in Stockholm, and his associates.

The study population included a total of 62,250 patients from the Finnish Hospital Discharge register who were treated for schizophrenia in the inpatient setting from 1972 to 2014. The median patient age was 45.6 years and the median length of follow-up was 14.1 years. Over the study period, 58.8% of this cohort were readmitted for psychiatric inpatient care, 67.2% used antipsychotic polypharmacy during the follow-up, and 57.5% were exposed to antipsychotic polypharmacy for at least 90 days, Dr. Tiihonen and his associates wrote in JAMA Psychiatry.

The combination of aripiprazole and clozapine was associated with the lowest risk of psychiatric rehospitalization, compared with those who received no therapy (hazard ratio, 0.42, 95% confidence interval, 0.39-0.46). Clozapine alone was the most effective antipsychotic monotherapy (HR, 0.49; 95% CI, 0.47-0.51), and when aripiprazole/clozapine was compared with clozapine alone, the polytherapy was significantly more effective (HR, 0.86; 95% CI, 0.79-0.94).

The difference between aripiprazole/clozapine and clozapine alone was even greater in patients who initially were hospitalized for their first episode of schizophrenia (HR, 0.78; 95% CI, 0.63-0.96). Overall, any antipsychotic polypharmacy was associated with a 7%-13% lower risk of hospitalization, compared with any monotherapy; clozapine alone was the only monotherapy among the 10 most effective treatments, the authors noted.

 Aripiprazole/clozapine combo more effective than monotherapies

Возможные механизмы антидепрессивного действия антипсихотиков второго поколения

Although the exact mechanism of SGAs for MDD has not yet been clearly elucidated, several plausible underlying mechanisms are listed as follows: modulation of crucial neurotransmitter receptors and transporters such as dopamine, serotonin and noreinephrine resulting in net effect of enhancement of such neurotransmitters' transmission, effects on sleep, alteration of various hormones (ACTH, sex hormones, etc.), modification of immune functions including modulation of inflammation process (cytokines, etc.), antioxidation process and modulation of neurotrophic factors (BDNF, etc).[13]

Specifically, the main pharmacological rationale of SGAs as an antidepressant augmentation would be based on their effects on monoamine transporters or receptors of crucial neurotransmitters such as serotonin, norepinephrine and dopamine, which are also the main target of contemporary antidepressants. The partial agonism at D2 and/or D3 receptors may increase dopamine neurotransmission at the prefrontal cortex. The increase in the dopamine concentration in the prefrontal cortex may be also indirectly related to the antidepressive effect of 5-HT1A receptor agonist.[14,15] The antidepressant effect may also be mediated by 5-HT1A partial agonism and/or antagonism at 5-HT2A receptors.[16–18] Although, still controversial, the antidepressant effect of 5-HT1A receptor agonists may be predominantly mediated by postsynaptic 5-HT1A receptors, while the anxiolytic effect would be mainly associated with presynptic 5-HT1A receptors.[19] The antagonism of the 5-HT2C receptors has been also found to be involved in increased dopamine and norepinephrine transmission.[20] It is also well known that high affinity at the α2-adrenergic receptor may enhance the release of norepinephrine.[21] Unlike any other SGAs, ziprasidone was reported to block synaptic serotonin, norepinephrine and dopamine reuptake in vitro.[22,23] Evidence indicates that both 5-HT6 agonists and antagonists may evoke identical responses in animal models of MDD, although the possible mechanisms of these effects seem to be diverse and are not clearly understood. The augmented effects were notable by combining antidepressants with a selective 5-HT6 receptor antagonist.[24] There is also a considerable amount of evidence supporting a role for the 5-HT7 receptor in MDD. The blockade of the 5-HT7 receptor led to antidepressant-like effects in animal models of MDD. It should be also worthy to mention that augmentation of 5-HT7 receptor antagonists with antidepressants was remarkable in animal models of MDD.[25]

Another mechanism involving in the action of SGAs should be the alteration of the glutamate receptor activity, and thus restoring normal glutamatergic neurotransmission and reducing the chances of excitotoxicity.[26] Some SGA treatment may also cause a decrease in plasma adrenocorticotropic hormone concentration and a normalization of HPA-axis dynamics.[27] An impaired neuroprotection has also been implicated in the pathophysiology of MDD.[28,29] Interestingly, activation of the 5-HT1A receptors was shown to be neuroprotective against various brain insults such as N-methyl-daspartic acid.[30] Some SGAs have also demonstrated such neuroprotective effects indicating a potential role in the protection against excitotoxicity in vivo.[30]

Overall 5-HT2A antagonism should be a commonly shared biological relevance for most of the SGAs as a potential mechanism of their antidepressant effect. Interactive effects with the dopaminergic system may be more distinct with the action mechanism of amisulpride and aripiprazole, while norepinephrine- and/or serotonin-reuptake inhibition should be the unique case with quetiapine or ziprasidone.[31] Each antipsychotic has a distinct profile of affinities towards different neurotransmitter receptors, which should be associated mainly with mediation of antidepressant-like effects.

Second-generation Antipsychotics in the Treatment of Major Depressive Disorder

Не связанные с дофамином механизмы действия антипсихотиков

APs suppress induction of pro-inflammatory cytokines. It is well established that psychotic episodes of schizophrenia are associated with neuroinflammation and elevations of cytokines such as interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and interferon gamma (IFN-γ). These inflammatory biomarkers are released by microglia, which are rapidly activated by psychosis and mediate brain tissue damage during psychosis. APs’ rapid inhibitory action on pro-inflammatory cytokines obviously is neuroprotective.
APs suppress immune-inflammatory pathways. This occurs with atypical agents but not haloperidol and results in decreased IL-1β and IL-6 and transforming growth factor-β.
APs significantly decrease levels of neurotoxic tryptophan catabolites (TRYCATS) such as 3-OHK and QUIN, which mediate the immune-inflammatory effects on neuronal activity. APs also increase levels of neuroprotective TRYCATS such as kynurenic acid.
APs activate cholesterol-transport proteins such as apolipoprotein E (APOE).6 This implies that APs may improve low levels of APOE observed during psychosis and decrease myelination abnormalities and mitigate impairment of synaptic plasticity.
APs increase neurotrophic growth factors that plummet during psychosis, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor. This beneficial effect is seen with SGAs but not first-generation APs (FGAs) and is attributed to strong serotonin 5HT-2A receptor antagonism by SGAs.
SGAs but not FGAs significantly increase the number of newly divided cells in the subventricular zone by 200% to 300%. This enhancement of neurogenesis and increased production of progenitor cells that differentiate into neurons and glia may help regenerate brain tissue lost during psychotic episodes.
Various SGAs have neuroprotective effects:
Clozapine has neuroprotective effects against liposaccharide-induced neurodegeneration and reduces microglial activation by limiting production of reactive oxygen species (free radicals).
Aripiprazole inhibits glutamate-induced neurotoxicity and, in contrast to haloperidol, increases BDNF, glycogen synthase kinase (GSK)-β, and the anti-apoptotic protein Bcl-2.
Olanzapine increases BDNF, GSK-3β, and β-catenin, increases mitosis in neuronal cell culture, and protects against neuronal death in cell cultures that lack nutrients (which fluphenazine or risperidone do not).
Paliperidone demonstrates a higher antioxidant effect than any other SGA and clearly is better than haloperidol, olanzapine, or risperidone in preventing neuronal death when exposed to hydrogen peroxide.
Quetiapine, ziprasidone, and lurasidone have inhibitory effects on nitric oxide release. Quetiapine, but not ziprasidone, inhibits TNF-α.
Ziprasidone inhibits apoptosis and microglial activation and synthesis of nitric oxide and other free radicals.
Lurasidone increases BDNF expression in the prefrontal cortex of rodents.

 Beyond dopamine: The ‘other’ effects of antipsychotics

Целесообразность потенцирования атипичными антипсихотиками при депрессии

For the study, researchers reviewed 14 previous randomized clinical trials in which the combined use of an antidepressant and an antipsychotic medication were compared to the use of an antidepressant with a placebo.

The medications investigated in the studies were aripiprazole (Abilify), olanzapine/fluoxetine (Symbyax), quetiapine (Seroquel) and risperidone (Risperdal).

The results showed a small benefit with antipsychotic use on relieving the symptoms of depression. But when the researchers looked for a more meaningful outcome — whether the patients’ quality of life had improved — no benefit was found.

...

Antipsychotic medications were associated, however, with more negative side effects, including weight gain, akathisia (a feeling of restlessness), sleepiness and abnormal results from cholesterol and other metabolic-related laboratory tests.

In another study, British researchers found strong evidence that engaging in talk therapy was an effective add-on to antidepressants.

The findings showed that antidepressant-resistant patients who received cognitive behavioral therapy in addition to an antidepressant experienced both a significant reduction in their depression and a significant improvement in their quality of life.

Adding Antipsychotic Meds to Antidepressants Shows Risk, Little Benefit

Механизм резистентности к лечению шизофрении

Scientists have discovered a molecular mechanism for resistance to antipsychotic medications, a finding that may pave the way for the development of new drugs to treat a significant proportion of schizophrenia patients who do not respond to these medications.

Investigators led by Javier González-Maeso, PhD, assistant professor of psychiatry and neurology, Mount Sinai School of Medicine in New York City, found that long-term administration of atypical antipsychotic drugs selectively upregulates expression of the enzyme histone deacetylase 2 (HDAC2) in both mouse and human frontal cortex.

This epigenetic change, which is dependent on serotonin 5-hydroxytryptamine 2A (5-HT2A) upregulation, leads to lower expression of the metabotropic glutamate 2 receptor (mGlu2), thereby limiting the therapeutic effects of atypical antipsychotic therapy, often leading to a recurrence of psychotic symptoms.

According to investigators, blocking this cascade of events with HDAC inhibitors may improve responses to atypical antipsychotic drug therapy.

"Together, these data suggest that HDAC2 may be a new therapeutic target to augment the treatment of schizophrenia.... Specifically, our findings encourage the development and testing of HDAC2-selective inhibitors for schizophrenia," the investigators write.

 New Discovery Raises Hope for Drug-Resistant Schizophrenia

Исследования новых антипсихотиков: илоперидон, карипразин

Several trends dominated new research on antipsychotic medications presented at the 2012 American Psychiatric Association (APA) meeting and the 2012 New Clinical Drug Evaluation Unit (NCDEU) meeting sponsored by the American Society of Clinical Psychopharmacology. Data on the management of negative and cognitive symptoms of schizophrenia with antipsychotic depot injectables used either alone or with an adjunctive therapy are growing steadily, and a number of posters focused on that trend. In addition, long-term data were presented for several newer antipsychotics, both in schizophrenia and bipolar depression. Leslie Citrome, MD, MPH, commented on the data in an interview with Medscape shortly after the 2 meetings.

 Recent Research in Antipsychotics

Профиль препарата JNJ-37822681

JNJ-37822681 is a novel, fast-dissociating dopamine D2 receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D2 receptor occupancy by variable single doses of JNJ-37822681, an open-label [11C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D2 receptor occupancy. Receptor occupancy increased from 9–19% at 2 mg doses to 60–74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.

In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography 

Using the rate of dissociation from the D2 receptor as a means to screen novel compounds for antipsychotic drug candidates, the centrally acting and fast-dissociating selective dopamine D2 receptor antagonist JNJ-37822681 was developed. In a blinded, placebo-controlled, randomized first-in-human study, JNJ-37822681 was administered orally to 27 healthy male volunteers at doses of 0.5, 2, 5, 10, 15 and 20 mg. Safety, pharmacokinetics and central nervous system effects were evaluated by measuring prolactin levels, eye movements, adaptive tracking, visual analogue scales, body sway, finger tapping and electroencephalography. JNJ-37822681 was well tolerated and somnolence was the most frequently reported adverse effect. Peak plasma concentrations increased more than proportional to dose, but increases in the area under curve (AUC) were dose-proportional. Prolactin elevations started at doses of 5 mg, whereas small decreases in adaptive tracking were demonstrated at 10 mg doses. At higher doses, JNJ-37822681 caused a small decrease in saccadic peak velocity, smooth pursuit, alertness, finger tapping and electroencephalography activity, and an increase in body sway. This effect profile is likely to be the result of the selectivity of JNJ-37822681 for the D2 receptor, leading to strong D2 receptor-mediated elevations in serum prolactin, but fewer effects on more complex central nervous system functions, which are likely to involve multiple neurotransmitters.

Pharmacokinetics and central nervous system effects of the novel dopamine D2 receptor antagonist JNJ-37822681 

Фармакодинамика антипсихотика SB-773812

The aim of this study was to assess human striatal dopamine receptor 2 (D2) and cortical 5-hydroxytryptamine receptor 2A (5-HT2A) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics–receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials.
Methods: D2 and 5-HT2A occupancy were measured over time (both at the time of maximum [Tmax; 6 6 2 h] and at the time of minimum [Ttrough; 24 6 4 h] plasma concentration after dosing) by means of 123I-iodobenzamide and 123I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide (123I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers—D2 occupancy measured at 48 (n 5 9) and 56 mg (n 5 9) and 5-HT2A occupancy at 56 mg (n 5 9); study B consisted of D2 and 5-HT2A occupancy measured in 12 stabilizedschizophrenia patients on stable doses (16–18 d of 56 mg/d) after washout of previous medication; and study C included D2 occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n 5 10) on stable doses (18–21 d) of SB-773812 (100 mg/d; n 5 7) or risperidone (6 mg/d; n 5 3).
Results: Study A showed less than 30% D2 occupancy at Tmax, maintained at Ttrough. 5-HT2A occupancy was 74%–97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D2 occupancy. 5-HT2A occupancy ranged from 91% to 100%. In study C, SB-773812–induced D2 occupancy was 60.3% 6 13.3% at Tmax and 55.1% 6 4.9% at Ttrough. The pharmacokinetics–receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC50) of 92.7 6 13.5 ng/mL for D2 and 2.11 6 0.50 ng/mL for 5-HT2A.
Conclusion: In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D2 occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics–receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.

 Contribution of SPECT Measurements of D2 and 5-HT2A Occupancy to the Clinical Development of the Antipsychotic SB-773812

Празозин как препарат выбора при ночных кошмарах в структуре ПТСР

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented. In open-label trials, a chart review, and placebo-controlled trials,prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo. In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.

 PTSD nightmares: Prazosin and atypical antipsychotics

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

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

... 

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

Adherence Better With Clozapine and LAI Antipsychotics

Генетические маркеры метаболических осложнений при приёме антипсихотиков второго поколения

Using DNA analysis, the researchers found that 8% of all study participants had the MTHFR C677T gene variant. Those with the variant who also used SGAs were significantly more likely to have metabolic syndrome than the children receiving SGAs but without the variant (OR, 5.75; P < .05).
The children with the gene variant also had higher diastolic blood pressure (P = .005) and higher fasting plasma glucose (P < .05).
"This is the first report of an underlying biological factor predisposing children to complications associated with SGA medication use. However, we need to do more research before this can be translated into clinical practice," said Dr. Panagiotopoulos.
She noted that because it is known that the MTHFR gene is involved in metabolizing the B-vitamin folate, the investigators are currently taking a more detailed dietary history from these children and conducting a study to answer "what's going on?" with the population's nutritional intake.

New Predictors May Determine Metabolic Risk in Kids on Atypicals

Исследование вторичной негативной симптоматики при приёме антипсихотиков

OBJECTIVE: Despite the clinical observation that antipsychotics can produce negative symptoms, no previous controlled study, to our knowledge, has evaluated this action in healthy subjects. The present study assessed observer-rated and self-rated negative symptoms produced by conventional and second-generation antipsychotics in healthy volunteers. METHOD: The authors used a double-blind, placebo-controlled trial of single doses of haloperidol (5 mg) and risperidone (2.5 mg) in normal subjects. Thirty-two subjects were administered haloperidol, risperidone, and placebo in a random order. Motor variables and observer-rated negative symptoms were assessed after 3–4 hours and subjective negative symptoms and drowsiness after 24 hours. RESULTS: Neither of the active drugs caused significant motor extrapyramidal symptoms after administration. Haloperidol caused significantly more negative signs and symptoms than placebo on the Scale for the Assessment of Negative Symptoms (SANS) and two self-rated negative symptom scales: the Subjective Deficit Syndrome Scale total score and an analog scale that evaluates subjective negative symptoms. Risperidone caused significantly more negative signs and symptoms than placebo on the Brief Psychiatric Rating Scale (BPRS), the SANS, the Subjective Deficit Syndrome Scale total score, and the analog scale for subjective negative symptoms. After control for drowsiness, risperidone but not haloperidol produced more negative symptoms than placebo on the BPRS and the SANS. Significance was lost for the subjective negative symptoms with both drugs. CONCLUSIONS: Single doses of both haloperidol and risperidone produce negative symptoms in normal individuals. Drowsiness may be an important confounding factor in the assessment of negative symptoms in antipsychotic trials.

Negative Signs and Symptoms Secondary to Antipsychotics: A Double-Blind, Randomized Trial of a Single Dose of Placebo, Haloperidol, and Risperidone in Healthy Volunteers

РКИ варениклина при шизофрении

The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2–8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline–placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p=0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p=0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p=0.008) and Stroop Interference (p=0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.

Adjunctive Varenicline Treatment with Antipsychotic Medications for Cognitive Impairments in People with Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Предупреждение нежелательных эффектов лекарственных препаратов в психиатрии

How to prevent adverse drug events

Депо-формы классических антипсихотиков превосходят по эффективности пролонгированную форму рисперидона

In a large population-based cohort study, conventional depot antipsychotics turned out to be superior to risperidone long-acting injection, Danish researchers reported here at the New Clinical Drug Evaluation Unit (NCDEU) 51st Annual Meeting, sponsored by the American Society of Clinical Psychopharmacology.

Older Antipsychotics Trump Newer Agents for Schizophrenia

Депо-формы антипсихотиков при первом эпизоде шизофрении

OBJECTIVE: Data on the effectiveness of antipsychotics in the early phase of schizophrenia are limited. The authors examined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2,588 consecutive patients hospitalized for the first time with a diagnosis of schizophrenia between 2000 and 2007 in Finland.

METHOD: The authors linked national databases of hospitalization, mortality, and antipsychotic prescriptions and computed hazard ratios, adjusting for the effects of sociodemographic and clinical variables, the temporal sequence of the antipsychotics used, and the choice of the initial antipsychotic for each patient.

RESULTS: Of 2,588 patients, 1,507 (58.2%) collected a prescription for an antipsychotic during the first 30 days after hospital discharge, and 1,182 (45.7%, 95% confidence interval [CI]=43.7–47.6) continued their initial treatment for 30 days or longer. In a pairwise comparison between depot injections and their equivalent oral formulations, the risk of rehospitalization for patients receiving depot medications was about one-third of that for patients receiving oral medications (adjusted hazard ratio=0.36, 95% CI=0.17–0.75). Compared with oral risperidone, clozapine (adjusted hazard ratio=0.48, 95% CI=0.31–0.76) and olanzapine (adjusted hazard ratio=0.54, 95% CI=0.40–0.73) were each associated with a significantly lower rehospitalization risk. Use of any antipsychotic compared with no antipsychotic was associated with lower mortality (adjusted hazard ratio=0.45, 95% CI=0.31–0.67).

CONCLUSIONS: In Finland, only a minority of patients adhere to their initial antipsychotic during the first 60 days after discharge from their first hospitalization for schizophrenia. Use of depot antipsychotics was associated with a significantly lower risk of rehospitalization than use of oral formulations of the same compounds. Among oral antipsychotics, clozapine and olanzapine were associated with more favorable outcomes. Use of any antipsychotic was associated with lower mortality.

A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia

Риски и преимущества перехода на терапию одним антипсихотическим препаратом

The study did find that treatment discontinuation was more common in the group that switched to monotherapy than in the polypharmacy group, but the symptom control and weight loss associated with the switch to monotherapy suggests that monotherapy may be an option worth trying for patients who are relatively stable.

Monotherapy After Polypharmacy Effective for Some Patients

Справочная информация по смене антипсихотиков, антидепрессантов и комбинированию нормотимиков

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Механизмы действия новейших антипсихотиков

Early pharmacotherapeutic agents used for schizophrenia targeted neuronal pathways related to psychosis. One of the first pharmacologic agents used in the treatment of patients with schizophrenia was the antihypertensive agent reserpine. The antipsychotic effects of this drug result from reduction of synaptic dopamine release.

For those who believe that focusing on these variations in neuropharmacologic binding effects is of minor importance, recall that the first effective antiobsessive, the tricyclic antidepressant chlomipramine, differs from imipramine by only 1 chloride atom substitution.31 It was hard to believe that chlomipramine would be effective for obsessive-compulsive disorder (OCD) when imipramine was not, but that is, in fact, what happened.

Iloperidone is an antipsychotic that was approved in May 2009 for the acute treatment of schizophrenia in adults. The mechanism of action, which involves antagonism of serotonin-2A (5HT-2A) and dopamine 2 receptors with a high 5HT-2A/D2 ratio, is similar to other atypical antipsychotics. Its efficacy appears to be similar to haloperidol, risperidone, and ziprasidone. It also has a very low EPS and akathisia profile, for reasons that are not well understood. It has strong alpha-adrenergic antagonism effects, and therefore requires a cautious dosing and titration schedule to reduce the potential for orthostatic hypotension and dizziness. The lack of affinity of iloperidone for other receptors (e.g., histamine, muscarinic) results in a low antihistaminic and anticholinergic side effect profile.37

Asenapine, approved for acute and maintenance treatment of schizophrenia, has a unique human receptor signature with binding affinities and antagonistic properties that are substantially different from other available schizophrenia treatments. Asenapine, which is administered sublingually, is a potent antagonist at several serotonin receptors38 and also has high affinity for alpha-adrenergic and dopaminergic receptors, which suggests potential for both antipsychotic and cognitive-enhancing properties.39 Clinical trial data demonstrate strong efficacy for positive symptoms, and there is some evidence of beneficial effects on negative and cognitive symptoms.

Expanding the Treatment Paradigm in Patients With Schizophrenia: Beyond Psychotic Symptoms

Эффективность атипичных антипсихотиков при делирии

Haloperidol is the mainstay of delirium treatment.8 Compared with atypical antipsychotics in delirium treatment, haloperidol doses < 3.5 mg/d have not been associated with an increase in extrapyramidal symptoms (EPS).9

Although not devoid of side effects, atypical antipsychotics are an alternative to haloperidol.8,10 This article briefly summarizes the current evidence on the use of atypicals for treating delirium.

Evidence for antipsychotics

Haloperidol has been the antipsychotic of choice for treating delirium symptoms. It is recommended by the Society of Critical Care Medicine7 and is regarded as safe, cost-effective, and efficacious for delirium5 despite a risk of dose-related EPS and potential cardiac conduction alterations.5,14

Risperidone is not indicated for treating delirium but is one of the most extensively studied atypical antipsychotic alternatives to haloperidol. Evidence consisting primarily of case reports has illustrated the potential efficacy of risperidone in treating delirium (Table 2).10,15-19

Clinical Point

In a small double-blind, randomized trial, risperidone was effective but not significantly more so than low-dose haloperidol

In 2004, Parellada et al17 observed significant mean improvements in all measures (Delirium Rating Scale [DRS], Mini-Mental State Exam [MMSE], positive subscale of the Positive and Negative Syndrome Scale [PANSS-P], and Clinical Global Impressions scale [CGI]) in 64 delirium patients treated with risperidone. In a 2004 double-blind trial of 28 delirium patients randomly assigned to risperidone or haloperidol, risperidone was effective but not significantly more efficacious than low-dose haloperidol for acute delirium treatment.18

Advantages of using risperidone include its lack of anticholinergic effects. Potential side effects include dose-related EPS and weight gain, which were observed in patients with schizophrenia and other psychotic disorders and dementia-related behavioral disorders.20,21

Olanzapine. Much like risperidone, olanzapine’s use in delirium is relatively well described in the literature (Table 3).22-24 In a randomized, placebo-controlled study comparing olanzapine with haloperidol, 175 patients were treated for 7 days with olanzapine, haloperidol, or placebo. Olanzapine and haloperidol showed significantly greater DRS score improvement than placebo.24 There was no difference between olanzapine and haloperidol outcomes; however, olanzapine showed significant improvement by days 2 and 3 compared with haloperidol. Haloperidol was associated with a significantly higher rate of dystonia compared with olanzapine.

Olanzapine carries a risk of anticholinergic effects. This can be a drawback, especially in patients such as Ms. B whose delirium has an anticholinergic component. Olanzapine is available in an IM formulation, which can be an advantage when addressing agitation and medical comorbidities of delirium.

Quetiapine. Case reports have suggested quetiapine is effective for delirium (Table 4).10,25-27 In a prospective, open-label trial, Sasaki et al26 treated 12 delirium patients with a single bedtime dose of quetiapine. All patients achieved remission within several days of beginning quetiapine, and the drug was well tolerated with no detected EPS or excessive sedation.

Clinical Point

Quetiapine reduced delirium duration and agitation in a small double-blind randomized trial of adult ICU patients

In 2010 Devlin et al27 reported on the efficacy and safety of quetiapine in a prospective double-blind, placebo-controlled study of 36 adult ICU patients. Compared with those receiving placebo, patients taking quetiapine had a statistically significant shorter time to first resolution of delirium, reduced duration of delirium, and less agitation as measured by the Sedation-Agitation Scale. Mortality, ICU length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to be discharged home or to rehabilitation and to have more somnolence. Quetiapine’s side effect profile includes a low occurrence of EPS, sedation, and dose-related anticholinergic effects.25

Ziprasidone. The literature on ziprasidone for delirium so far is limited to a few anecdotal case reports (Table 5).28-31 In 2002, Leso and Schwartz28 successfully used ziprasidone to treat delirium in a patient with human immunodeficiency virus and cryptococcal meningitis. Ziprasidone was chosen for its lack of sedating effects and low EPS risk. The patient experienced significant clearing of his delirium and lowering of his DRS score. Ziprasidone eventually was discontinued because a fluctuating QTc interval associated with comorbid electrolyte imbalances—a potential drawback to ziprasidone.

In the case of Ms. B, ziprasidone appeared to be efficacious; however, improvement in her medical condition, rather than ziprasidone treatment, is the most likely explanation for the resolution of her delirium symptoms.

Aripiprazole. Alao et al30 reported on 2 delirium patients treated with 30 mg and 15 mg aripiprazole; improvement was monitored using the MMSE and DRS (Table 5).28-31 In both cases, confusion, disorientation, and agitation improved within 7 days of treatment. In the first case, the patient’s MMSE score improved from 5 to 28 and his DRS score decreased from 28 to 6. The second patient’s MMSE score improved from 7 to 27 and her DRS score went from 18 to 6.

Straker et al31 reported on 14 delirium patients treated with aripiprazole. Twelve patients had a ≥50% reduction in DRS, Revised-98 scores, and 13 showed improvement on CGI scores. The rate of adverse side effects was low. Three patients had prolonged QTc interval, but no patients developed arrhythmia or discontinued aripiprazole.

Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?