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

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

Комбинация эсциталопрама с арипипразолом в терапии коморбидной депрессии алкогольной зависимости

 The effective treatment of depression has been reported to reduce the severity of alcohol use, potentially reflecting improvements in common brain reward circuits. We hypothesized that augmentation therapy of escitalopram with aripiprazole would improve depressive symptoms as well as reduce craving for alcohol and cue-induced brain activity in patients with co-morbid alcohol dependence and major depressive disorder, compared with treatment with escitalopram alone. Thirty-five subjects with major depressive disorder and alcohol dependence were recruited and randomly assigned into 17 aripiprazole + escitalopram and 18 escitalopram only groups. At baseline and following six weeks of treatment, symptoms of depression, craving for alcohol and brain activity were evaluated. During the six week treatment period, Beck Depression Inventory and clinical global index-severity (CGI-S) scores decreased in both the aripiprazole + escitalopram and escitalopram only groups. In addition, following the treatment period, the Korean alcohol urge questionnaire scores in the aripiprazole + escitalopram group were reduced from 23.3±8.4 to 14.3±4.9, compared with those of the escitalopram group of from 21.6±8.4 to 19.3±7.1 ( F=13.1, p < 0.01 ). The activity within the anterior cingulate was increased in response to the presentation of alcohol drinking scenes following treatment in the aripiprazole + escitalopram group. The change of brain activity within the left anterior cingulate gyrus in all patients with co-morbid alcohol dependence and major depressive disorder was negatively correlated with the change in craving for alcohol. These findings suggest that the effects of aripiprazole on anterior cingulate cortex might mediate the successful treatment of alcohol dependence in patients with major depressive disorder.

Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: Clinical and neuroimaging evidence

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

Арипиразол, кветиапин и оланзапин в терапии биполярной депрессии

Seven published papers were identified on the use of aripiprazole, olanzapine and quetiapine. Internal validity of the trials was fairly good, external validity only moderate. Different outcome measures of efficacy and safety were assessed. When the individual trials were looked at, quetiapine and to a lesser extent olanzapine demonstrated significant improvement in MADRS (Montgomery–Åsberg Depression Rating Scale) total scores. This was not demonstrated for aripiprazole. Efficacy was hampered by adverse events, such as weight gain, akathisia and somnolence/sedation. Both clinical heterogeneity of the included trials and statistical heterogeneity of the meta-analytic data were considerable. The number of quetiapine trials was disproportionate to the number of trials of aripiprazole and olanzapine. Further research is needed to assess differential efficacy of the different SGAs and their use in clinical practice.

Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis

Метаболические расстройства коморбидные с БАР

Chronic stress, which patients experience during both the manic and the depressive phases of bipolar disorder, is associated with increased cortisol levels, lack of cortisol suppression, and changes in hypothalamic-pituitary-adrenal axis responses. This metabolic dysregulation may increase insulin resistance and can lead to hyperglycemia, increased oxidative stress, metabolic syndrome, and atherosclerosis. In addition, patients with bipolar illness have increased activity of the sympathetic nervous system, which may also lead to insulin resistance, metabolic syndrome, and increased risk of sudden cardiac death.2

Depressive syndromes may be neurotoxic. Abnormalities in cellular plasticity, cellular resilience, and intracellular signaling, as well as alterations in the size, shape, and density of neurons and glia, have been found. Studies employing neuroimaging and neuropsychological tests have demonstrated abnormalities in brain morphology and function in patient populations with depressive syndromes and in those with diabetes. Common physiologic mechanisms have been implicated, including insulin-glucose homeostasis, immuno-inflammatory processes, and oxidative stress mechanisms.


Metabolic Comorbidities in Patients With Bipolar Disorder

Significant Weight Gain Associated with Post-Clozapine Antipsychotics

Significant Weight Gain* Associated with Post-Clozapine Antipsychotics
*≥7% body weight increase vs placebo; 4-8 week trials

Стратегии лечения тиков при синдроме Туретта

The majority of treatment options for tics are pharmacological. The most commonly prescribed drugs are primarily dopamine antagonists, such as neuroleptics (e.g. haloperidol), benzamides (e.g. sulpiride) or atypical antipsychotics (e.g. risperidone). Other agents that may be efficacious include drugs which modulate noradrenaline (e.g. clonidine), GABA (e.g. benzodiazepines) and acetylcholine (e.g. nicotine). Nonpharmacological interventions include behavioural approaches such as habit reversal training and exposure response prevention therapy. Surgical techniques involving deep brain stimulation (DBS) of the thalamus or globus pallidus may also be considered for severe, treatment refractory patients. Some of the more recent treatments that have been trialled include electroconvulsive therapy and repetitive transcranial magnetic stimulation.

.
Treatment Strategies for Tics in Tourette Syndrome

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?

Антипсихотики второго поколения в терапии депрессии

Abstract

Purpose of review The aim of this systematic review was to examine the efficacy and safety of second-generation antipsychotics (SGAs) in nonpsychotic major depressive disorder (MDD).
Recent findings In MDD, SGA monotherapy or adjunctive therapy to conventional antidepressants showed rapid onset of antidepressant efficacy. Although maintenance data are limited, quetiapine monotherapy, risperidone adjunctive therapy, and amisulpride adjunctive therapy significantly delayed the time to relapse as compared with placebo. In general, extrapyramidal symptoms appeared to be low with SGAs, but a higher incidence of akathisia was observed with aripiprazole. An elevated risk of weight gain was observed with olanzapine–fluoxetine combination, risperidone, aripiprazole, and quetiapine compared with placebo. At present, there are insufficient data to confidently distinguish between different SGAs in the treatment of MDD. A recent meta-analysis found that adjunctive SGAs were significantly more effective than placebo, but differences in efficacy were not identified among the studied agents, nor were outcomes affected by trial duration or the method of establishing treatment resistance.
Summary Both SGA monotherapy and adjunctive therapy showed greater efficacy in the treatment of MDD than placebo, but augmentation is more widely utilized in treatment-resistant depression. Clinicians should routinely monitor for cardiometabolic side-effects and extrapyramidal symptoms during SGA therapy.

Quetiapine

The efficacy and safety of QTP-XR monotherapy in the treatment of MDD were evaluated in two 8-week, placebo-controlled RCTs.[7••,8•] In the first trial, QTP-XR 150 or 300 mg/day and duloxetine 60 mg/day were compared with placebo.[7••] All active treatment arms demonstrated significant improvement in Montgomery–Asberg Depression Rating Scale (MADRS)[27] total scores compared with that of placebo at week 6. Significant improvement in depressive symptoms occurred at the end of week 1 with both QTP-XR 150 mg/day (−8.4, P < 0.01) and 300 mg/day (−8.2, P < 0.01) compared with placebo (−6.0), but not duloxetine 60 mg/day (−6.8, P = 0.30). At study endpoint (week 6), remission rates (MADRS ≤ 8) were significantly higher in the QTP-XR 300 mg/day (32.0%, P < 0.05) and duloxetine 60 mg/day groups (31.9%, P < 0.05) vs. placebo (20.4%), but not for QTP-XR 150 mg/day (26.5%, P = 0.27).
Sulpiride and Amisulpride

Apart from QTP-XR, SLP and ASLP are the only other SGAs that have been studied as monotherapy treatment for MDD in placebo-controlled trials. A moderately sized (n = 88) study found greater reduction in the 21-item Hamilton Depression Rating Scale (HAM-D-21)[28] total score from baseline to endpoint in the SLP group (−10, P = 0.0007) than in placebo (−8). The only RCT of ASLP in the acute treatment of MDD compared a fixed dosage of ASLP 50 mg/day (n = 136) with paroxetine 20 mg/day (n = 136).[11] No statistically significant differences occurred between the two treatments, but a placebo group was not included to establish internal validity.[11] A long-term (6-month), fixed-dosage, placebo-controlled RCT in mild or moderate MDD or dysthymia compared the efficacy and safety of ASLP (50 mg/day) with imipramine (100 mg/day) and placebo.[12] Analysis of the primary outcome showed the mean change in MADRS total scores in both active treatment arms was significantly larger than that of placebo, although remission rates did not reach the level of statistical significance.

Second-generation Antipsychotics in Major Depressive Disorder: Update and Clinical Perspective

Психоз при потенцировании дулоксетина арипипразолом

"Ms. L" was a 49-year-old woman with chronic depression and postoperative cellulitis following a bunion excision. She was evaluated on the medical unit. She endorsed depressive symptoms, auditory hallucinations, and suicidal thoughts. The patient had previously attempted suicide twice by drug overdose. Her most recent suicide attempt was 7 months prior. Previous responses to sertraline and citalopram were poor. At the time of assessment on the medical unit, she was receiving duloxetine (40 mg twice daily), aripiprazole (1 mg/day), clonazepam (1 mg twice daily), and amoxicillin/clavulanate (850 mg twice daily).

The patient was started on duloxetine 7 months before. Ten days prior to admission, her primary care physician had started her on aripiprazole (2 mg/day) for augmentation. She denied a history of psychotic symptoms and drug or alcohol abuse as well as a family history of psychosis.

Three days after starting aripiprazole, Ms. L reported auditory hallucinations. She was paranoid regarding her ex-husband. She described command hallucinations from the devil, who meant to harm her, and could also hear God's voice encouraging her not to listen to the devil. She experienced concurrent onset of suicidal ideation with no plan. She was fully oriented, with no evidence of confusion. Aripiprazole was reduced to 1 mg/day, which led to amelioration of her hallucinations. However, her suicidal thoughts and paranoid beliefs persisted.

The psychiatric consultant decided to discontinue aripiprazole, leading to rapid and complete resolution of the patient's psychotic symptoms and suicidal ideation. Her ongoing depression was managed with duloxetine (60 mg twice daily).

New-Onset Psychosis and Emergence of Suicidal Ideation With Aripiprazole

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

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

Генотипы CYP450 и эффекты антипсихотиков

Metabolism of most antipsychotics depends on the CYP450 enzyme system, which is expressed predominantly in the liver (Table 1). CYP2D6 is one of these enzymes and may be responsible for metabolizing approximately 20% to 50% of all medications, including a number of antipsychotics.2 Genetic variations of CYP2D6 are common and the frequencies of these variants differ among racial groups.3

The half-life and other pharmacokinetic parameters of an antipsychotic metabolized by CYP2D6 may differ based on whether someone is a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM).4 Regarding CYP2D6 metabolism among Whites, 3% to 5% are UMs, 70% to 80% are EMs, 10% to 17% are IMs, and 5% to 10% are PMs.5 By contrast, the percentage of PMs and UMs in the Asian population is low—about 1% for each phenotype; the IM phenotype is more common (65% to 70% in the Chinese population).5,6 The percentage of PMs in African Americans is roughly 2% to 6%.2

Cytochrome P450 (CYP) metabolism of commonly used antipsychotics*

Drug	CYP1A2	CYP2C9	CYP2C19	CYP2D6	CYP3A4/5
Aripiprazole				X	X
Asenapine	X			X	X
Chlorpromazine	X			X	X
Clozapine	X	X	X	X	X
Fluphenazine				X
Haloperidol	X			X	X
Iloperidone				X	X
Olanzapine	X			X
Paliperidone				X†	X†
Perphenazine	X	X	X	X	X
Quetiapine				X	X
Risperidone				X	X
Thioridazine			X	X
Ziprasidone	X				X
*Information obtained from the most recent prescribing information available from each drug’s manufacturer †According to paliperidone’s prescribing information, in vitro studies identify that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, but in vivo studies indicate that their role in eliminating paliperidone is minimal

Figure: Effects of CYP2D6 poor metabolizer status on the half-life of risperidone, aripiprazole, and iloperidone

EM: extensive metabolizer; PM: poor metabolizer
Source: References 7-9

It is not known if obtaining genotype information will provide better outcomes than a ‘trial and error’ approach

Should you order genetic testing to identify how patients metabolize antipsychotics?

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

Атипичность атипичных антипсихотиков

The main reason for the development of atypical antipsychotics was to provide an antipsychotic treatment option that was free of EPS and, further, to reduce the risk of tardive dyskinesia. Although many agents now claim to be atypical, the data presented suggest that only clozapine and quetiapine are true atypical antipsychotics. Of the available agents, clozapine and quetiapine show the lowest affinity for and the most rapid release from D2 receptors.3 As a result, clozapine and quetiapine have been shown to have an incidence of EPS that was no different from placebo across the full dosage range.4
Promotion of risperidone, olanzapine, ziprasidone, and possibly aripiprazole has emphasized the atypicality of these agents; however, based on the data presented here, one should question whether these agents are truly atypical antipsychotics. Both risperidone and olanzapine have demonstrated EPS levels similar to placebo at low doses; at higher doses, however, EPS incidence for both agents becomes greater than with placebo.4 Data for ziprasidone are limited; however, ziprasidone appears to have an EPS risk similar to that of risperidone and olanzapine.56,57 Ari-piprazole has been associated with akathisia; however, further study and experience with this drug are needed before definitive conclusions can be drawn.

Atypicality of Atypical Antipsychotics

Арипипрозол для коррекции нейролептик-индуцированной гиперпролактинемии

OBJECTIVE: Hyperprolactinemia and associated side effects often occur with antipsychotics. The authors investigated the effect of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in patients with schizophrenia maintained with haloperidol. METHOD: Fifty-six patients with hyperprolactinemia taking haloperidol were enrolled. Haloperidol dose was fixed; aripiprazole was dosed at 15 mg/day for the first 4 weeks, then 30 mg/day for the following 4 weeks. Serum prolactin, haloperidol, and aripiprazole levels were measured. Symptoms and side effects were assessed with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms, Clinical Global Impression symptom scale, Simpson-Angus Rating Scale, and Barnes Akathisia Rating Scale at weeks 1, 2, 4, 6, and 8. RESULTS: Prolactin levels of patients receiving aripiprazole significantly decreased over time, demonstrating a significant time effect and a time-by-group interaction. In the aripiprazole group, 88.5% of patients at week 8 had prolactin levels normalize compared to 3.6% of patients receiving placebo. Among 11 female patients with menstrual disturbances randomly assigned to aripiprazole, seven patients regained menstruation during the study, whereas none receiving placebo did. Plasma levels of haloperidol were not significantly altered. No significant time effect and time-by-group interactions on BPRS, Scale for the Assessment of Negative Symptoms, and Simpson-Angus Rating Scale scores were noted. CONCLUSIONS: Adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes, resulting in reinstatement of menstruation in female patients, with no significant effects on psychopathology and extrapyramidal symptoms. Aripiprazole has higher affinity to dopamine D2 receptors than haloperidol, which is the likely cause of this observation.

Adjunctive Treatment With a Dopamine Partial Agonist, Aripiprazole, for Antipsychotic-Induced Hyperprolactinemia: A Placebo-Controlled Trial

Микседематозная кома вызванная комбинацией арипипразола и сертралина

Myxedema Coma Associated with Combination Aripiprazole and Sertraline Therapy
Chelsea O Church, PharmD BCPS

Associate Professor of Pharmacy Practice, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK

Erin C Callen, PharmD BCPS

Associate Professor of Pharmacy Practice, College of Pharmacy, Southwestern Oklahoma State University

Reprints: Dr. Church, Department of Pharmacy Practice, Southwestern Oklahoma State University College of Pharmacy, Pasteur Medical Building, Pharmacy Education, 1111 North Lee, Ste. 241, Oklahoma City, OK 73103, fax 405/601-1201, chelsea.church@swosu.edu

OBJECTIVE: To describe a case of myxedema coma (MC) associated with combination aripiprazole and sertraline therapy.

CASE SUMMARY: A 41-year-old male presented to the emergency department with confusion, right-sided numbness and tingling, slurred speech, dizziness, and facial edema. His blood pressure was 160/113 mm Hg, with a pulse of 56 beats/min and temperature of 35.4 °C. Initial abnormal laboratory values included creatine kinase (CK) 439 U/L; serum creatinine 1.6 mg/dL; aspartate aminotransferase 85 U/L; and alanine aminotransferase 35 U/L. Repeat cardiac markers revealed an elevated CK level of 3573 U/L with a CK-MB of 24 ng/mL. Thyroid function tests showed thyroid-stimulating hormone 126.4 µIU/mL and free thyroxine 0.29 ng/dL. Home medications of unknown duration were sertraline 200 mg and aripiprazole 20 mg daily. He was admitted to the intensive care unit and initially treated with intravenous levothyroxine and dexamethasone. By hospital day 4, the patient was clinically stable and discharged to home.

DISCUSSION: Myxedema coma, the most significant form of hypothyroidism (HT), is a rare but potentially fatal condition. The known precipitating causes of MC were ruled out in this patient, which left his home medications as the likely cause. Cases of HT caused by certain atypical antipsychotics and antidepressants are found in the literature, but none was reported with aripiprazole therapy. There are also no reported cases of sertraline or aripiprazole inducing MC. Use of the Naranjo probability scale indicates that the combination of aripiprazole and sertraline was a probable inducer of MC in this patient.

CONCLUSIONS: Due to the widespread use of psychotropic medications, clinicians should be reminded of the rare, yet life-threatening, occurrence of MC when treating patients, especially with combination therapies such as sertraline and aripiprazole.

Myxedema Coma Associated with Combination Aripiprazole and Sertraline Therapy