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

Бензонат натрия как усилитель NMDA в лечении резистентной шизофрении

To the authors’ knowledge, this is the first study to demonstrate benefits of an NMDA enhancer in patients with clozapine-resistant schizophrenia. Sodium benzoate at both 1g and 2g/day was more effective than placebo in improving negative symptoms, and this medication had a favorable safety profile. Sodium benzoate 2g/d also improved total psychopathology and quality of life scores.

The authors noted the relatively small sample size and short trial duration as potential study limitations and call for additional studies of both doses of sodium benzoate in longer trials. They concluded that DAAO inhibitors may represent a novel treatment approach for patients with clozapine-resistant schizophrenia.

Food Preservative for Schizophrenia?

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

Различия в действии антипсихотиков на обсессивно-компульсивную симптоматику при шизофрении

Indirect evidence supports the assumption that antiserotonergic second-generation antipsychotics (SGA) induce and aggravate obsessive–compulsive symptoms (OCS) in schizophrenia. However, multimodal studies assessing the long-term interaction of pharmacotherapy and psychopathology are missing. Over 12 months, we followed-up 75 schizophrenia patients who were classified into two groups according to antipsychotic treatment: clozapine or olanzapine (group I) versus aripiprazole or amisulpride (group II). We applied the Yale Brown Obsessive Compulsive Scale (YBOCS) and investigated between-group changes over time as the primary endpoint. Group I showed markedly higher YBOCS scores at both time points. Repeated measure analyses of variance (ANOVAs) revealed significant interaction effects of group and time (per protocol sample (PP): p=0.006). This was due to persistently high OCS severity within group I, and decreasing YBOCS scores within group II. OCS severity correlated significantly with the negative and general psychopathology subscales of the Positive and Negative Syndrome Scale (PANSS), as well as with depressive symptoms. The progressive differences in OCS severity between our groups support the assumption of differential pharmacodynamic effects on comorbid OCS in schizophrenia. Further studies should address the pathogenetic mechanism, define patients at risk and facilitate early detection as well as therapeutic interventions.

Differential effects of antipsychotic agents on obsessive–compulsive symptoms in schizophrenia: a longitudinal study

Психофармакологические тесты в диагностике аффективных расстройств

Таким образом, для выбора адекватной терапии приступов аффективных психозов необходимо понять структуру состояния больного, отражающую механизмы образования его синдрома. Для этой цели клинический метод успешно дополняется психофармакологическими тестами. Лечение аффективных и аффектив­но-бредовых больных (кроме маниакальных) целесообразно начи­нать с пробного терапевтического курса анксиолитиками (феназепамом, лепонексом) или с диазепамового теста. В зависимости от трансформации клинической картины, указывающей на основ­ное биологическое расстройство, на «блок», являющийся основой патологического состояния, в дальнейшем назначаются антиде­прессивные или энергизирующие препараты. Создается впечатление,  что сфера применения нейролептиков в терапии аффективных приступов должна быть весьма ограниченной рамками маниакаль­ных и маниакально-параноидных состояний, в комбинации с нормотимиками.

 Точилов В.А. - ОБ ИССЛЕДОВАНИИ СТРУКТУРЫ И ЛЕЧЕНИИ АФФЕКТИВНЫХ ПРИСТУПОВ

Стратегии потенцирования действия клозапина

Background. When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder.

Methods. Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g). Results. Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal.

Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.

Conclusions. Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

 Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

Клозапин, нейтропения и гранулоцитарный фактор, стимулирующий рост клеток

Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

 Granulocyte Colony Stimulating Factor (G-CSF) can allow treatment with clozapine in a patient with severe Benign Ethnic Neutropaenia (BEN): a case report

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

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

Сравнение атипичных антипсихотиков

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

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

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

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

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

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

Потенциирование клозапина: сульпирид, амисульприд, ламотриджин

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

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

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

Management of clozapine-resistant schizophrenia

Normally, after eating, your body uses carbohydrate as the main energy source. After a long time hungry, it switches to fat. Zyprexa made the body use fat all the time

SUMMARY: A class effect, to varying degrees; and eating less may not help.


1. Food intake was the same between controls and Zyprexaers. You get these effects even if you eat the same.

2. This effect is shared by other atypicals, in a predictable fashion:


In the fed state, Zyprexa and Clozaril do a massive conversion to fat utilization, Risperdal a medium, and sulpiride minimal covnersion.

In the fasting state:

Geodon has a lesser effect than Zyprexa, and appears to normalize; Abilify and Haldol seem close to normal.

3. These effects are consistent with Lilly's own studies that the majority of weight gain happens in the first month, and not suddenly after a year of use.

4. There is still a hunger component to weight gain that is separate from the metabolic effect. Some drugs will make you hungry, change your metabolism, or some mixture of the two. Hunger appears to be a H1 mediated process (Seroquel, Zyprexa, Clozaril, Remeron, Paxil>Prozac, etc.)

5. The immediate clinical consequence of this information is probably (paradoxically) to tell the patients to eat less sugar.

Unless you dramatically cut fat out of your diet, the body will still churn through what fat you do eat at the expense of carbohydrate. Better, and easier, to reduce the carb load that lingers in your body (and likely ultimately gets stored.)

Why Zyprexa (And Other Atypical Antipsychotics) Make You Fat

Клозапин

• Indian research: Focus on clozapine
• Relapse of tardive dyskinesia due to reduction in clozapine dose

Ошибочно диагностированная шизофрения у пациента с эпилепсией

One of the subjects that most concerns physicians is treatment-resistance. About 30%–60% of schizophrenia patients do not respond adequately to antipsychotic treatment and are known as refractory schizophrenia patients. Clozapine has been the drug of choice in such cases. However, approximately 30% of them do not respond to clozapine either. Here, we describe a patient with an initial diagnosis of refractory schizophrenia who had a history of dramatic aggressiveness. However, in this case, “refractoriness” was a wrong diagnosis. A case of psychosis secondary to epilepsy had been treated as schizophrenia for almost 20 years. Reports like this one are important because they remind us of how a thorough investigation can lead to the correct diagnosis and improve the patient's prognosis.

A False Case of Clozapine-Resistant Schizophrenia

Подбор доз антипсихотиков второго поколения

Drug-drug interactions or genetic variability may require using doses different from those recommended for atypical antipsychotics. Dosage alterations of olanzapine and clozapine, dependent on cytochrome P450 1A2 (CYP1A2) for clearance, and quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Smoking cessation can significantly increase clozapine, and perhaps olanzapine, levels. Ziprasidone pharmacokinetic drug-drug interactions are not likely to be important. Genetic variations of cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing. Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or aripiprazole. Adding inducers may be associated with a gradual development of lost efficacy.

The Dosing of Atypical Antipsychotics

This higher ratio means that smokers need three to four times the caffeine "dosage" as nonsmokers on average to get the same plasma caffeine levels...
Thus smoking or caffeine intake should not influence the dosing of risperidone and aripiprazole (metabolized by CYP2D6 and CYP3A), quetiapine (mainly metabolized by CYP3A), and ziprasidone (mainly metabolized by an aldehyde oxidase and CYP3A). On the other hand, the metabolism of clozapine and olanzapine is mainly dependent on CYP1A2 and UGTs. Table 1 summarizes studies that describe smoking's effects on the dosing of clozapine and olanzapine. Because caffeine has the opposite effect of smoking and increases the levels of clozapine and olanzapine, studies of caffeine interactions are also reviewed in the table. The effects of caffeine on CYP1A2 are explained by competitive inhibition. The effects of inhibitors are seen sooner than those of inducers, which require CYP1A2 synthesis...
The width of the therapeutic window determines the clinical significance of the plasma level changes associated with smoking and caffeine intake. Compared with olanzapine, clozapine has a much narrower therapeutic window...
Table 1 provides an average smoking correction factor of 1.5 for clozapine. If a patient who is taking clozapine smokes, smoking cessation would probably cause an average patient's plasma clozapine level to increase by 1.5 two to four weeks later. Similarly, if a patient who is stabilized in a nonsmoking environment starts to smoke more than one pack a day, the clinician may need to consider increasing the clozapine dose by a factor of 1.5 over two to four weeks. Checking for side effects and measuring the clozapine level may then be prudent, because the 1.5 factor is a gross approximation.

Gender may also influence clozapine metabolism. The limited information available (3,4) suggests that an average female nonsmoker requires low clozapine dosages (around 300 mg per day) to reach therapeutic levels, whereas an average male heavy smoker requires high dosages (around 600 mg per day). The required dosages for male nonsmokers and female smokers fall in between these numbers. Obviously, these are average results and may not apply to specific individuals. In the future, it is hoped that a better understanding of genetics may help to individualize clozapine doses. A CYP1A2 genetic variation may influence how patients respond to smoking's inductive effects. However, in a recent study this variation did not have any effects on clozapine levels in the clinical environment (5).
Table 1 shows that the average caffeine correction factor is .6 for clozapine. Assuming other variables are stable, including no changes in smoking patterns, if a patient whose clozapine dose is stabilized in a caffeine-free environment begins to regularly consume high quantities of caffeine, it may be safest to decrease the clozapine dose—for example, from 400 to 250 mg a day (400 mg a day x .6=240 mg a day). Only high quantities of caffeine seem to have significant clinical interactions with clozapine.

In the United States, brewed coffee is estimated to contain 85 mg of caffeine per 5 oz cup; instant coffee, 65 mg per 5 oz cup; decaffeinated coffee, 3 mg per 5 oz cup; tea, 40 mg per 5 oz cup; and caffeinated sodas, including caffeinated colas, 40 mg per 12 oz can. In Europe, brewed coffee is estimated to contain more caffeine (100 mg per 150 cc cup). Obviously, caffeinated over-the-counter medicines in pill form may have much more caffeine than caffeinated beverages (up to 200 mg per pill). No data are available that show what level of caffeine intake is safe for patients who are taking clozapine. Steady caffeine dosages for a patient who is stabilized and is taking clozapine should not be of concern for clinicians. However, it may be important to warn the patient to avoid "dramatic" changes—either up or down —in caffeine intake. However, no published data define "dramatic" change in caffeine intake.
Psychopharmacology: Atypical Antipsychotic Dosing: The Effect of Smoking and Caffeine

Селективность антипсихотиков in vitro и ex vivo

In a recent human [11C]-(+)-PHNO positron emission tomography study, olanzapine, clozapine, and risperidone occupied D2 receptors in striatum (STR), but, despite their similar in vitro D2 and D3 affinities, failed to occupy D3 receptors in globus pallidus. This study had two aims: (1) to characterize the regional D2/D3 pharmacology of in vitro and ex vivo [3H]-(+)-PHNO binding sites in rat brain and (2) to compare, using [3H]-(+)-PHNO autoradiography, the ex vivo and in vitro pharmacology of olanzapine, clozapine, risperidone, and haloperidol. Using the D3-selective drug SB277011, we found that ex vivo and in vitro [3H]-(+)-PHNO binding in STR is exclusively due to D2, whereas that in cerebellar lobes 9 and 10 is exclusively due to D3. Surprisingly, the D3 contribution to [3H]-(+)-PHNO binding in the islands of Calleja, ventral pallidum, substantia nigra, and nucleus accumbens was greater ex vivo than in vitro. Ex vivo, systemically administered olanzapine, risperidone, and haloperidol, at doses occupying ~80% D2, did not occupy D3 receptors. Clozapine, which also occupied ~80% of D2 receptors ex vivo, occupied a smaller percentage of D3 receptors than predicted by its in vitro pharmacology. Across brain regions, ex vivo occupancy by antipsychotics was inversely related to the D3 contribution to [3H]-(+)-PHNO binding. In contrast, in vitro occupancy was similar across brain regions, independent of the regional D3 contribution. These data indicate that at clinically relevant doses, olanzapine, clozapine, risperidone, and haloperidol are D2-selective ex vivo. This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade.

The Antipsychotics Olanzapine, Risperidone, Clozapine, and Haloperidol Are D2-Selective Ex Vivo but Not In Vitro

Потенциирование, добавление второго антипсихотика или повышение доз атипичных антипсихотиков

The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone,and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating
schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.

Increasing the dose in patients with partial responses or breakthrough symptoms is faster and easier than switching to another agent, and it is possible that it would result in improved efficacy. There are also some patients who may be
rapid metabolizers, and thus require higher doses than the average patient. However, although some patients may benefit from higher doses, this method of treatment can
increase the risk of side effects, especially motor side effects. Positron emission tomography (PET) data demonstrate that dopamine 2 (D2) receptor occupancy of 70% is necessary for therapeutic benefits, while occupancy greater than 80% is associated with extrapyramidal symptoms [34]. Doses at the upper end of the recommended range for the first-line antipsychotics may already result in 80% occupancy of D2
receptors in the nigrostriatal pathway [35], so that doses above those ranges are more likely to induce EPS. In particular, the risk of EPS with risperidone is dose-
dependent and may even increase above 4 mg/day

In summary, there is currently no compelling evidence to support long-term antipsychotic polypharmacy. There are few theoretical benefits and many theoretical detriments. Although individual patients may respond to antipsychotic
polypharmacy without side effects, adequate trials have not yet determined the costs versus the benefits of this option.

The evidence for augmentation of atypical antipsychotics varies depending on the particular agent. Controlled studies with conventional antipsychotics suggest that augmentation with benzodiazepines is most likely useful as an acute treatment for patients with agitation and hostility, but controlled studies do not exist for atypical antipsychotics. As mentioned earlier, a multicenter double-blind study demonstrates the safety and efficacy of only one augmenting agent in schizophrenia, namely divalproex [96]. Controlled studies combining divalproex and an atypical antipsychotic also show additive benefits in bipolar disorder, strengthening the appeal of this particular augmenting strategy [167-168]. Unfortunately, there are no controlled data for augmentation of atypical antipsychotics with other anticonvulsants even though this is a frequent and expensive practice, especially with gabapentin. Thus, the evidence currently suggests that divalproex is perhaps the best evidence-based augmentation option when multiple monotherapies fail

A Critical Review of Atypical Antipsychotic Utilization: Comparing
Monotherapy with Polypharmacy and Augmentation

Рецепторный профиль анитипсихотиков второго поколения и галоперидола

Receptor Binding Profile of Aripiprazole and Reference Antipsychotics^a

Receptor	Aripiprazole	Olanzapine	Risperidone	Quetiapine	Ziprasidone	Clozapine	Haloperidol
D1	265b	31	430	455	525	85	210
D2	0.34b	11	4	160	5	126	0.7
D3	0.8b	49	10	340	7	473	2
D4	44b	27	9	1600	32	35	3
5-HT1A	1.7b	>10,000	210	2800	3	875	1100
5-HT2A	3.4b	4	0.5	295	0.4	16	45
5-HT2C	15b	23	25	1500	1	16	>10,000
a1	57	19	0.7	7	11	7	6
H1	61b	7	15	11	50	6	440
M1	>10,000	1.9	>10,000	120	>1000	1.9	>150

Aripiprazole in the Treatment of Schizophrenia

Успешное возобновление клозапина у пациентки с нейтропенией вызванной клозапином

S.P. was a 56-year-old African American man with a 30-year history of paranoid schizophrenia. He had sufficiently tolerated a clozapine rechallenge in 2007, 2 years after developing clozapine-induced neutropenia. Following a period of relative stability after the rechallenge, he discontinued treatment with clozapine because of complaints of dizziness and an unwitnessed syncopal episode, which were not clearly attributed to the drug. Shortly afterward, he suffered functional decline and required inpatient stabilization. He was initially titrated to haloperidol (20 mg/twice daily), olanzapine (20 mg/day), and divalproex sodium (750 mg/twice daily). Unfortunately, this regimen was ineffective, and he continued to exhibit bizarre behavior, severe paranoid delusions, social isolation, and an inability to conduct activities of daily living. In light of his improvement after the 2007 clozapine rechallenge, S.P. and his treatment team elected to initiate clozapine treatment again.

Clozapine Rechallenge in Refractory Schizophrenia