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The possibility of using the modern antipsychotic aripiprazole (Abilify) in borderline psychiatry and general somatic practice (literature review) No. 02 2010

Author: N.A. Ilyina

NTsPZ RAMS, Moscow

Page numbers in the issue: 45-48

Currently, an increasing number of studies are aimed at developing effective tactics for the treatment of anxiety and depressive disorders. At the same time, the choice of psychotropic drugs is more often based not so much on the use of antidepressants in monotherapy, but on the use of combination therapy with the use of modern antipsychotics. A lot of works have been devoted to the study of these drugs in the treatment of disorders observed in general somatic practice.

Currently, an increasing number of studies are aimed at developing effective tactics for the treatment of anxiety and depressive disorders. At the same time, the choice of psychotropic drugs is more often based not so much on the use of antidepressants in monotherapy, but on the use of combination therapy with the use of modern antipsychotics. A lot of works have been devoted to the study of these drugs in the treatment of disorders observed in general somatic practice. Their results showed a satisfactory safety and tolerability profile of new antipsychotics prescribed in optimal doses, taking into account the age of the patient and the characteristics of the course of the somatic disease [1, 2].
One such modern antipsychotic is aripiprazole (Abilify). It has been established that the combination of partial agonistic activity against dopamine D2- [3] and serotonin 5HT1A receptors with antagonistic activity against serotonin 5HT2A receptors [4] determines the therapeutic effect of aripiprazole in schizophrenia. In vitro experiments have shown that aripiprazole has a high affinity for dopamine D2- and D3-receptors, serotonin 5HT1A- and 5HT2A-receptors and a moderate affinity for dopamine D4-, serotonin 5HT2C- and 5HT7-, a1-adrenergic receptors and histamine h2 receptors. In addition, the effect of the drug is also characterized by a moderate affinity for serotonin reuptake sites and a lack of affinity for muscarinic receptors. Such a fairly wide pharmacodynamic profile ensures the effectiveness of aripiprazole therapy also in relation to manic states in type I bipolar disorder [5, 6]; studied the possibility of using aripiprazole in bipolar depression [7, 8]. More recently, the drug has been registered as an additional therapy for major depressive disorder in case of insufficient effectiveness of the antidepressants used [10-13].
The data of some authors, given below, suggest the effectiveness of aripiprazole not only in schizophrenia and affective pathology, but also in other (anxiety, obsessive-compulsive, personality - PD) disorders, often associated with somatic diseases.

Aripiprazole in RL therapy
Although the drug has no registered indications for the treatment of LC, some clinical data suggest the presence of pharmacological activity of the drug in personality pathology. As is known, the greatest need for the appointment of psychotropic drugs, in particular antipsychotics, occurs in borderline PD due to the variety of clinical manifestations.
So, when conducting a double-blind, placebo-controlled study to determine the effectiveness of aripiprazole (a sample that included 52 patients with borderline PD), M. Nickel et al. [14] concluded that aripiprazole at a dose of 15 mg/day provides a statistically significant improvement in the condition of patients compared with placebo.
It should be noted that among the comorbid disorders, patients were diagnosed with: depression (aripiprazole group: n=21 - 80.8%; placebo group: n=22 - 84.6%), anxiety disorders (aripiprazole group: n=16 - 61, 5%; placebo group: n=14 - 53.8%), obsessive-compulsive disorders (aripiprazole group: n=3 - 11.5%; placebo group: n=3 - 11.5%) and somatoform disorders (n= 18 - 69.2% and n=19 - 73.1%, respectively).
A decrease in the values ​​of indicators of obsessive-compulsiveness, hostility in social contacts, depression, anxiety, aggressiveness/hostility, phobic anxiety, paranoid thinking, psychomotor functions (scale SCL-90-R) was recorded. An analysis of formalized indicators on the same scale allowed the authors to state that the use of aripiprazole (treatment course for 8 weeks) is accompanied primarily by a reduction in depressive symptoms, while anxiety is subject to a gradual regression. At the same time, according to the Hamilton scales for depression and anxiety (HAM-D and HAM-A), the change in the total score during treatment with aripiprazole versus placebo was not statistically significant. In addition, aripiprazole therapy also contributed to the reduction of manifestations of anger (STAXI scales, which allow assessing the severity of this phenomenon).
In assessing the tolerability of the drug, the authors noted a number of the most common adverse events, including headache, insomnia, nausea, constipation and anxiety. It is important to note that a significant increase in body weight was not registered.
Thus, despite the relatively small sample size, as well as the short duration of the study, the authors concluded that aripiprazole may be effective as a means of not only reducing the symptoms of borderline PD, but also improving the quality of life of patients in terms of health. and interpersonal relationships.
This assumption was confirmed in the second (clinical and follow-up) part of the study by M. Nickel et al. [fifteen]. Patients with borderline personality disorder included in the above sample continued to receive aripiprazole at a dose of 15 mg/day for 18 months. The results of a long-term study showed that aripiprazole effectively affects not only depressive, but also dysphoric symptoms (anger, aggression), thereby stabilizing the condition of patients with borderline PD, which is characterized by affective imbalance with the detection of dysphoric outbreaks.

Aripiprazole in the treatment of anxiety and depressive disorders
The data on the effectiveness of aripiprazole in relation to anxiety symptoms in the structure of PD can be supplemented by data obtained from clinical observations, which more fully reveal the spectrum of pharmacological activity of this drug, extending to anxiety and comorbid depressive pathology.
So, D. Adson et al. [16] conducted a 9-week study evaluating the efficacy of aripiprazole in depressed patients with anxiety symptoms who received selective serotonin reuptake inhibitors (SSRIs) at stable dosages. The authors noted a significant reduction in all outcome measures after addition of aripiprazole. The study included 10 patients over 18 years of age with a diagnosis of unipolar depression or dysthymia and/or generalized anxiety disorder (GAD), panic disorder or phobic disorder, with a Hamilton Anxiety Scale (HAM-A) score of ≥16. Aripiprazole was prescribed at a starting dose of 5 mg/day with a further increase to a maximum (20 mg/day) by the 4th week. Mean Montgomery Asberg Scale (MADRS) scores decreased from baseline of 28.9±7.3 to 6.5±8.7 by the end of the study (p<0.001). The Sheehan Disability Scale (SDS) scores also decreased from 18.4 at baseline to 6.7 by the end of the study. The Hospital Anxiety and Depressions Rating Scale (HAD) score decreased from baseline 22. 8 to 9.3. An analysis of the values ​​of the anxiety and depression subscales of the HAD scale also revealed a decrease from 13.3 to 6.1 and from 9.0 to 3.2 points, respectively. When assessing the condition at the stage of follow-up 2 weeks after discontinuation of aripiprazole, some increase in symptoms was detected.

Adverse events were minor and resolved after a few days or weeks from the start of aripiprazole. The average increase in body weight of patients was about 3 kg. This fact, contrary to the prevailing idea of ​​the “neutrality” of aripiprazole in relation to changes in body weight, allowed the authors to suggest that in depression, including anxious symptoms, sensitivity to taking psychotropic drugs increases, and accordingly, there is a risk of weight gain during aripiprazole therapy. The authors also suggested that akathisia and other extrapyramidal symptoms in patients with affective disorders may be due to an increase in the concentration of aripiprazole when combined with antidepressants that have the ability to inhibit the CYP2D6 enzyme. Some limitations of the study were noted: open design, short duration, the possibility of a placebo effect and inadequate dosages of SSRIs.
M. Kellner [17] reported on a 25-year-old patient who, according to the DSM-IV criteria, was diagnosed with chronic post-traumatic stress disorder along with bipolar affective disorder after a series of massive psycho-traumatic effects. The clinical picture revealed signs of social phobias and trichotillomania. After repeated attempts at therapy with serotonergic antidepressants, as well as some atypical antipsychotics used in high doses, without significant improvement in the condition, in addition, sedation was noted. Administration of aripiprazole at a dose of 15 to 30 mg/day resulted in stabilization of mood, a significant reduction in anxiety, nightmares, and relief of symptoms of trichotillomania. When taking aripiprazole up to 45-60 mg / day (the patient increased the dose of the drug on her own), a further decrease in the severity of anxiety, dysphoric disorders and auto-aggression without sedation and other undesirable effects was noted. This observation led the authors to conclude that the use of aripiprazole "may be an available option for treatment-resistant patients with bipolar and/or post-traumatic stress disorder."

Aripiprazole in the treatment of schizophrenia with comorbid social phobia
R. Stern et al. [18] reported preliminary results from a study whose working hypothesis was that switching to aripiprazole reduces the severity of social phobias that develop within schizophrenia. The dynamics of psychopathological disorders was assessed using the Liebowitz Social Anxiety Scale (LSAS), Sheehan's Disability Scale (SDS), and the Lehman's Quality of Life Interview (B-QOLI) questionnaire - an abbreviated version. Pre-study neuroleptic therapy was gradually (by cross-titration) replaced with aripiprazole (maximum daily dose of 30 mg). Patients who completed the 8-week study in the acute phase were eligible to participate in the extended phase for a further 10 months. 9patients included in the extended phase, by the 12th month, there was a significant (compared to the values ​​on the 56th day of the study) decrease in social phobia scores (overall score on the LSAS scale, avoidance, anxiety), social disability (overall score on the Sheehan scale as well as work, social activity, and family items), general functioning and emotional well-being (B-QOLI), and psychotic symptoms (PANSS total score). The authors concluded that these preliminary data, indicating a reduction not only in psychosis, but also in social phobia, as well as an improvement in the quality of life of patients when switching to aripiprazole therapy, dictate the need for further research in this direction.

Aripiprazole add-on therapy study
J. Worthington et al. [19] reported an increase in the action of SSRIs with the addition of aripiprazole in 17 patients with treatment-resistant depression or anxiety, according to a retrospective, open-label pilot study. In 71% of patients, previous therapy with atypical antipsychotics was unsuccessful. The performance parameters in this study were the scores on the CGI-I and CGI-S scales.
Overall, the mean aripiprazole dosage was 17 mg (range, 7.5 to 30 mg/day) and the mean duration of therapy was 4.9 ± 3 weeks (range, 1 to 12 weeks). By the end of the study, the total scores on the CGI-S scale decreased significantly (from 5.4 to 3.8; p<0. 001). Therapeutic response, defined in CGI-I scores as "very marked improvement" or "marked improvement", was observed in 10 (59%) of 17 patients, according to the analysis of "intent-to-treat" (analysis of data from all patients, included in the study), in 8 (67%) of 12 patients who completed the study. Of the 17 patients, 5 prematurely discontinued participation in the study: 3 due to adverse events, 1 due to insufficient therapeutic effect, 1 due to economic reasons. In 5 of 17 patients, no adverse events were noted.
E.Hoge et al. [20] reported an 8-week, open-label, prospective, booster study investigating the efficacy and tolerability of aripiprazole in adult outpatients with GAD (n=13) or panic disorder (n=10) who also had somatovegetative disturbances despite for a previous at least 8 weeks of treatment with conventional methods of pharmacotherapy in adequate doses. As a result of the addition of aripiprazole, a significant reduction in psychopathological symptoms was achieved according to the CGIS-S scale (paired values ​​t=4. 41, df=22, p<0.001) in an intent-to-treat sample of 23 patients. The authors concluded that the findings suggest a possible use of an augmentation strategy in patients with GAD or panic disorder who show insufficient response to prior psychopharmacotherapy.

Aripiprazole for GAD
M.Menza et al. [21] in an open 6-week pilot study studied the possibility of increasing the effectiveness of treatment of therapeutically resistant GAD (comorbid depression was detected in 8 patients) by adding aripiprazole in 9 patients (18–65 years old). Aripiprazole was prescribed at a dose of 10 mg/day with subsequent adjustment according to tolerability and therapeutic response. The prescribed antidepressant, if necessary, was combined with benzodiazepines or sedative hypnotics at a stable dosage for 6 weeks.
Of the 9 patients, 8 completed the study. The Hamilton Anxiety Scale (HAM-A) score decreased from baseline 26.2 to 14 (p<0.0001), and 89% of patients had a CGI score of “marked improvement” or “very marked improvement” at the end of the study. ". 5 patients were assessed as HAM-A responders (score reduction by at least 50%), and 1 patient was in remission (HAM-A score <10). The mean dosage at the end of the study was 13.9mg/day Significant improvement was also noted in relation to depressive symptoms. Mean values ​​on the Hamilton Depression Rating Scale (HAM-D) were 21.6 points at baseline and 11.8 points at the end of the study (p=0.0004). The indicators of the SF-36 subscales also improved: social functioning, state of health, activity, emotional manifestations. At the same time, the SF-36 Physical Feeling Subscales and the Extrapyramidal Symptom Rating Scale (ESRS) scores remained unchanged. In 3 patients during the 1st week of therapy, the phenomena of akathisia were noted. Other mild to moderate adverse events included headache (1 patient), nausea (1), dizziness (1), fatigue and blurred vision (1), weight gain (10 lb gain), and increased anxiety (1 patient). ). All of these events (with the exception of weight gain) resolved in 8 patients who completed the study.
G.Kinrys et al. [22] studied the efficacy of aripiprazole in treatment of therapeutically resistant GAD with somatic and autonomic symptoms (tachycardia, cardialgia, nausea, etc.). In an open study, 12 patients (mean age 48.9 years, 66.7% women) with GAD who did not achieve a clinical response to adequate anxiolytic therapy received aripiprazole for 8 weeks. The primary outcome measures were Hamilton Anxiety Scale (HAM-A), CGI-S CGI-I. Completed research 9patients, of which 8 (88.8%) were regarded as responders. Intent-to-treat analysis (ITT - analysis of data from all patients included in the study) identified 9 (75%) responders. The total number of patients in remission (according to ITT) was 7/9 and 7/12.

The most frequently observed adverse events were sedation, fatigue, agitation and nervousness.
The authors concluded that aripiprazole may enhance the efficacy of anxiolytic therapy in patients with therapeutically resistant GAD with somatovegetative manifestations.
C. Rae et al. [23] presented a review of preclinical and preliminary data on the use of aripiprazole in the treatment of depressive and anxiety disorders. The authors indicate that clinical studies demonstrate the possibility of using aripiprazole in the treatment of bipolar depression, major depressive disorder, treatment-resistant depression, and possibly anxiety disorders. Moreover, clinical data show that aripiprazole has fewer side effects than other atypical drugs. The authors note that future studies may confirm the potential use of aripiprazole in the treatment of depressive and anxiety disorders.

Aripiprazole and HIV
Aripiprazole is the first drug approved by the FDA as an adjuvant in the treatment of depression, but the therapeutic response when using the drug in patients with HIV is not well understood. One of the few publications indicating that aripiprazole therapy can reduce the severity of depressive symptoms and improve immunoreactivity during antiretroviral therapy for HIV infection belongs to C. Cechelli et al. [24]. The authors present a casuistic observation in which they discussed a patient with a verified at 1997 HIV. Since then, he has received antiretroviral therapy. Blood tests showed a decrease in the number of CD4+ cells and a positive viral load. Since the spring of 2008, the patient began to experience attacks of trembling and nausea with vomiting, diarrhea, tremors and paresthesias. The condition was accompanied by complaints of headaches, dorsalgia, insomnia, fatigue, loss of appetite, performance, concentration. A fixation on the problems of his own health was revealed: he repeatedly turned to various specialists for help. Of the psychotropic drugs, he took lorazepam (3 mg/day), trimipramine (100 mg/day) for 8 weeks, paroxetine (20 mg/day) for 10 weeks, and mirtazapine (30 mg/day) for 12 weeks without clinical effect.
In September 2008, he was admitted to the hospital, where he was diagnosed with resistant depression, somatoform disorder (hypochondria) and panic disorder. Combination therapy with citalopram 40 mg/day and aripiprazole (up to 15 mg/day) was prescribed. During the treatment, the patient's depressive and somatoform symptoms were reduced, professional adaptation was restored. In parallel, hematological and immunological parameters improved (an increase in the number of CD4 cells and a negative viral load were recorded).
The authors believe that the addition of low doses of aripiprazole (up to 15 mg/day) increases the effectiveness of therapy in patients with symptoms of resistance to antidepressant monotherapy (SSRIs, tricyclic antidepressants), and indicate the prospect of further studying the effectiveness of aripiprazole in HIV-infected patients with concomitant depression.

Conclusion
The above data on the efficacy and tolerability of the modern antipsychotic aripiprazole can be considered as confirmation of the possibility of its use not only in schizophrenia, type I bipolar disorder and unipolar depression, but also as an adjuvant therapy in patients with anxiety disorders and psychosomatic disorders. Aripiprazole can also be used to correct a wide range of symptoms (obsessive-compulsive, dysphoric, etc.) observed in PD. Own data obtained in clinical practice can also serve as an additional argument in favor of the effectiveness of aripiprazole for the treatment of these conditions, and a favorable tolerability profile makes it possible to use this antipsychotic for the correction of psychopathological disorders in somatic patients.

Credits:
Ilyina Natalya Alekseevna - Dr. med. sciences, ved. scientific collaborator NCPZ RAMS. 115522, Moscow, Kashirskoe sh., 34;
tel. 8 499 616-18-56

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Aripiprazole

Chemical group: aripiprazole (Abilify) a quinolinone derivative.

Formulation: Aripiprazole is available in tablets of 2, 5, 10, 15, 20 and 30 mg

Pharmacokinetics: Aripiprazole has an average half-life of approximately 75 hours, so the drug can be administered once a day. The maximum concentration of aripiprazole in plasma is reached after 3-5 hours. Absolute bioavailability is 87%. Equilibrium concentration is reached after 14 days. The main metabolite of the drug is dehydroaripiprazole, has the same affinity for dopamine receptors as aripiprazole, its half-life is 94 o'clock.

Dosage regimen: starting dose of the drug 10-15 mg per day. The same dose is considered the minimum for the relief of acute exacerbation of schizophrenia.

Average daily therapeutic doses of aripiprazole correspond to 20-30 mg, maintenance therapy can be carried out at the level of 15-20 mg. After reaching the optimal dose of the drug (15-20 mg), its correction is usually carried out after 2-3 weeks. According to a number of authors, 30 mg should be considered the most effective daily dose of the drug.

A relatively low initial dose of the drug is especially necessary in elderly patients and in combination with other psychotropic drugs.

The drug can be taken at any time of the day, regardless of food intake.

Unlike some AAs, aripiprazole does not require dose adjustment in smokers and can also be used for renal and mild liver failure.

An injectable form of aripiprazole is currently being developed for intramuscular administration of the drug.

Mechanism of action: Aripiprazole is an atypical antipsychotic that increases dopamine activity in areas of the brain where it is reduced (mesocortical structures) and decreases dopamine activity in those brain structures where it is, on the contrary, increased (mesolimbic structures).

In the first case, the clinical effect of aripiprazole is manifested by a reduction in negative symptoms, in the second case, by relief of positive symptoms.

Aripiprazole is considered a stabilizer of the dopamine system and the first partial agonist of dopamine receptors (D2), but its stimulation of these receptors is somewhat inferior in intensity to the actual stimulation of dopamine. The concept of "partial agonist" emphasizes that the effect of aripiprazole depends on the initial state of the functional activity of the dopamine network.

Aripiprazole is also a serotonin 5HT2A antagonist and a partial serotonin 5HT1A receptor agonist, the first feature explains the absence of a decrease in the seizure threshold, the second is the presence of anxiolytic activity in this drug.

Aripiprazole shows moderate sensitivity to D4, 5HT2C, 5HT7, h2 receptors.

The peculiar mechanism of action of the drug avoids negative effects on the receptors of neurons in the nigrostriatal and tuberoinfundibular regions, manifested in extrapyramidal symptoms and hyperprolactenemia.

Thus, aripiprazole can be considered the first neuromodulator (stabilizer) in relation to the dopaminergic and serotonergic systems of the central nervous system.

Aripiprazole has moderate activity at alpha1-adrenergic, histamine and serotonin 5HT2C receptors.

Indications: the drug is distinguished by a pronounced reduction in positive and negative symptoms, cognitive impairment, stable maintenance of the effect with long-term use of the drug.

Aripiprazole has a distinct preventive and anti-relapse activity.

Indications for treatment of schizophrenia with aripiprazole

• Prevention of schizophrenia in boys over 18 years of age
• Severe manifestations of negative symptoms
• Severe manifestations of cognitive deficits, especially verbal memory impairment
• Supportive care
• Comorbid neurotic disorders, depressive spectrum disorders

While taking aripiprazole, there is a significant improvement in secondary verbal memory, one of the components that determine the primary and repeated reproduction, as well as the categorization of a list of words. Taking the drug enhances the activity of patients with schizophrenia, increases motivation, promotes the acquisition of new skills, improves the ability to solve social problems by regulating interpersonal relationships.

In comparative studies of the effectiveness of the drug with an antipsychotic such as haloperidol, aripiprazole was comparable in terms of the strength of the effect, but markedly outperformed in terms of safety of use.

At the same time, some authors noted an increase in the severity of mania among the adverse clinical effects of aripiprazole. Some authors note the effectiveness of aripiprazole in the presence of psychotic seizures that are not accompanied by psychomotor agitation, pronounced affects of fear and anxiety (Ivanov M.V. et al., 2007).

American psychiatrists note the effectiveness of aripiprazole in the treatment of patients with borderline disorder (according to the DSM1V classification).

Aripiprazole reduces the severity of depressive symptoms.

Side effects: the absence of daytime sleepiness and lethargy in 90% of patients treated with aripiprazole makes it attractive to many patients. However, at a dosage of 15 mg, sedation and drowsiness may occur in 10% of patients, at the level of 30 mg, similar symptoms were recorded in 15% of patients.

Side effects of aripiprazole:

• Psychiatric disorders: mania, anxiety (25%)
• Neurological disorders: headache (32%), insomnia (24%), dizziness (11%), akathisia (10%)
• Gastroenterological disorders: nausea (14%), vomiting (12%), constipation (10%)
• Rare cardiovascular disorders: vasovagal syndrome, arrhythmias

The drug does not increase weight, the level of prolactin in the blood. Due to the fact that aripiprazole, as a rule, blocks less than 70% of dopamine D2 receptors, it practically does not cause extrapyramidal symptoms, which, on average, are recorded only in 6-13% of cases, more often manifesting as tremor and akathisia.

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