Journal of Addictive Diseases

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/wjad20

Atypical antipsychotics in the treatment of

patients with a dual diagnosis of schizophrenia
spectrum disorders and substance use disorders:
the results of a randomized comparative study

V. Yu. Skryabin, M. A. Vinnikova, E. V. Ezhkova, M. S. Titkov & R. A. Bulatova

To cite this article: V. Yu. Skryabin, M. A. Vinnikova, E. V. Ezhkova, M. S. Titkov & R. A. Bulatova
(2021): Atypical antipsychotics in the treatment of patients with a dual diagnosis of schizophrenia
spectrum disorders and substance use disorders: the results of a randomized comparative study,
Journal of Addictive Diseases, DOI: 10.1080/10550887.2021.1905589

To link to this article: https://doi.org/10.1080/10550887.2021.1905589

Published online: 09 Apr 2021.

Submit your article to this journal

Article views: 63

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=wjad20
JOURNAL OF ADDICTIVE DISEASES
https://doi.org/10.1080/10550887.2021.1905589

Atypical antipsychotics in the treatment of patients with a dual diagnosis of

schizophrenia spectrum disorders and substance use disorders: the results of
a randomized comparative study
V. Yu. Skryabin, MDa,b , M. A. Vinnikova, PhD, MDa,c, E. V. Ezhkova, MDa, M. S. Titkov, PhD, MDd and
R. A. Bulatova, MSca
a
Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia; bRussian Medical
Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russia; cScientific
Department, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov
University), Moscow, Russia; dPsychiatry and Psychotherapy Division, European Medical Centre, Moscow, Russia

ABSTRACT KEYWORDS
The article presents the results of a randomized comparative study of Aripiprazole and Schizophrenia; substance
Quetiapine in the treatment of patients with a dual diagnosis: schizophrenia and substance use disorders; craving; dual
use disorders. During the study, 90 of the 266 male patients were screened. Among them, diagnosis; PANSS; BPRS;
VAS; atypical antipsychotics
54 individuals (60%) had a previously established diagnosis of mental disorder and 36
patients (40%) had no established psychiatric diagnosis. They were randomly randomized
into three groups of 30 patients, each receiving an antipsychotic: Aripiprazole at a dose of
up to 20 mg daily, Quetiapine at a dose of up to 600 mg daily, or Haloperidol at a dose of
up to 30 mg daily. The efficacy of Aripiprazole and Quetiapine was evaluated using the fol-
lowing scales: PANSS, BPRS, VAS, and Substance Craving Scale (SCS). Drug safety was
assessed by the development of adverse events, serious adverse events, or adverse reac-
tions. Study results demonstrated the efficacy of atypical antipsychotics in the three groups.
Analysis of independent variables showed significant differences between Aripiprazole and
Haloperidol in PANSS and BPRS scores by Visit 4, in VAS scores by Visit 3, and in SCS scores
by Visit 2. Intergroup analysis of independent variables showed significant differences
between Quetiapine and Haloperidol in PANSS, VAS, and SCS scores by Visit 4. Intergroup
analysis of independent variables showed significant differences between Aripiprazole and
Quetiapine in the VAS and SCS scores. The correlation analysis allowed drawing conclusions
about the close connection of the symptoms of schizophrenia and substance use disorders
in patients with a dual diagnosis

Introduction According to DSM-5, Schizophrenia spectrum

The problem of dual diagnosis is widely discussed by and other psychotic disorders include schizophre-
researchers, since the combined course of the two nia, other psychotic disorders, and schizotypal
disorders causes both differential diagnosis-related (personality) disorder. They are defined by
and treatment-related difficulties, and has a rather abnormalities in one or more of the following
poor prognosis for the development of qualitative five domains: delusions, hallucinations, disorgan-
remissions.1 In the population, there is an increase in ized thinking (speech), grossly disorganized or
the number of people suffering from combined abnormal motor behavior (including catatonia),
forms of mental and substance use disorders.2 Of and negative symptoms. Although criteria and
most significant interests are issues related to the text for schizotypal personality disorder can be
combined course of substance use disorder and found in the “Personality Disorders” chapter of
schizophrenia spectrum disorders, such as slow pro- DSM-5, since this disorder is considered part of
gressive forms of schizophrenia or schizotypal per- the schizophrenia spectrum of disorders, and is
sonality disorder. labeled in this section of ICD-9 and ICD-10 as a

CONTACT Valentin Yurievich Skryabin, MD [email protected] Moscow Research and Practical Centre on Addictions of the Moscow Department
of Healthcare, 37/1 Lyublinskaya Street, Moscow 109390, Russia
ß 2021 Taylor & Francis Group, LLC
2 V. YU. SKRYABIN ET AL.

schizotypal disorder, it is listed in the chapter France, Italy, the Netherlands, and the United
“Schizophrenia spectrum and other psychotic dis- Kingdom) have reported an increase in multiple
orders” and discussed in detail in the DSM-5 drug use and an increase in the number of deaths
“Personality Disorders” chapter. from a combination of morphine, benzodiaze-
Epidemiological evidence shows that nearly pines, and alcohol.15 In Russia, the same pattern
half of patients with schizophrenia spectrum dis- is observed: epidemiological data from recent
orders develop substance use disorders through- years indicate that the overall incidence of mental
out their lives, whereas about a third of them and behavioral disorders due to multiple drug
begin to abuse alcohol, and about a quarter use use and use of other psychoactive substances
drugs.3 Conversely, substance use is thought to (F19, ICD-10) is increasing. The proportion of
increase the risk of developing a schizophrenic patients with the diagnosis of F19, according to
process4; meanwhile, patients with a dual diagno- ICD-10, was 8.3% in 2013, 10.6% in 2014, and
sis demonstrate an earlier age of schizophrenic 15.8% in 2015.16
process manifestation.5 Until now, there is no Studies on the psychotherapeutic and pharma-
single universal etiopathogenetic model to explain cological treatment of patients with dual diagno-
the relationship between schizophrenia spectrum sis are so diverse in terms of patient
disorders and substance use disorders.6 characteristics, treatment methods, and disorder
One way or another, mental illness is associ- outcomes that two comparable studies can hardly
ated with an increased risk of substance depend- be found.14 Accordingly, the results of treatment
ence syndrome development.7 Some studies have remain disappointing. In the treatment of
found that patients using more than three psy-
patients with a dual diagnosis, the most effective
choactive substances are significantly more likely
results are obtained when a combination of anti-
to suffer from schizophrenia and bipolar affective
psychotic therapy and rehabilitation programs
disorder than patients using only one substance.8
is used.17,18
Various forms of schizophrenia are three times
Recent publications have noted the efficacy of
more common in the population of alcohol- and
antipsychotics in patients with schizophrenia and
cannabis-use disorder patients than in people
comorbid alcohol use disorder.19 Patients with a
who do not use drugs.9 Cannabis use by mentally
dual diagnosis who participate in substitution
ill people is associated in most cases with an early
therapy programs and receive atypical antipsy-
onset of schizophrenia5 and a higher risk of
relapse after the first psychotic episode.10 chotics showed better remission results than
Sensitization to stress in patients with endogen- patients receiving typical antipsychotics.20 The
ous processes at an early age has been suggested authors emphasize that successful treatment of
to increase the risk of substance misuse.11 such patients can only be achieved by combining
Psychotic disorders due to substance use, such traditional antipsychotic therapy with simultan-
as amphetamines or cannabis, are often consid- eous treatment of substance use disorder.21
ered risk factors for schizophrenia.12,13 A meta- There is growing evidence in the scientific lit-
analysis conducted between 1990 and 2017 found erature that the use of atypical antipsychotics in
that 41.7% of patients with schizophrenia spec- patients with a dual diagnosis allows for effective
trum disorders use drugs in forms ranging from management of psychopathological symptoms,
episodic harmful use to substance use disorders, reduction of craving, reduction in the number of
with 27.5% using illicit drugs (such as opioids), early relapses, and, in the long run, an improve-
26.2% using cannabis (permitted in some coun- ment of the quality of remissions.22–27
tries for medical purposes), 24.3% using alcohol, Meanwhile, positive treatment results are
and the remaining 22% using other substances.14 observed not only in patients with a dual diagno-
Currently, there is an increase in the global sis but in patients with different variants of sub-
prevalence of multiple drug use. This trend has stance use disorders also.28–32 However, it should
been marked since the early 2000s when a num- be noted that not all of the results are unambigu-
ber of countries in Western Europe (Spain, ous, and there are studies in which the
 JOURNAL OF ADDICTIVE DISEASES 3

effectiveness of atypical antipsychotics is not consent to a psychiatrist consultation. Exclusion

confirmed.33–37 criteria: the craving to a single psychoactive sub-
Two atypical antipsychotics of the greatest stance; craving to gambling; acute illness or acute
research interest are Quetiapine and Aripiprazole, state of chronic diseases; positive HIV status;
which are now widely used in psychiatric prac- positive Wassermann reaction; more than 3-fold
tice, and have also shown high efficacy and safety increase in ALT and AST levels.
in the treatment of both mental disorders38–42
and dependence syndrome.43,44 General description of research methods
Quetiapine is an atypical antipsychotic with its
own antidepressant effect38 and a favorable safety The ASI (Addiction Severity Index) tool was used
profile; it has a weak affinity for D1 and D2 for a comprehensive assessment of the medical,
receptors, a high affinity for 5-HT2 receptors, and psychological, and social conditions of patients
blocks alpha-adrenal receptors to some extent. with substance use disorders.45
Aripiprazole is an atypical antipsychotic with a To objectify the data related to the diagnosis
unique pharmacological profile that includes par- of schizophrenia spectrum disorders, the severity
tial agonism at D2- and 5HT1a-receptors, antag- of positive and negative symptoms, as well as to
onism at 5-HT2-receptors, and agonism at evaluate the efficacy of the medications, the fol-
presynaptic D2-autoreceptors. Thus, it can lowing scales were used: BPRS (Brief Psychiatric
increase and reduce dopamine levels in certain Rating Scale),46,47 with PANSS (P) as a scale
brain regions. of positive syndromes, PANSS (N) as a scale of
negative syndromes, and PANSS (O) as a scale of
general psychopathology.
Study objective To objectify the data related to the dynamics
The objective of the present study was to investi- of psychopathological symptoms in the structure
gate the efficacy and safety of Quetiapine and of substance use disorders, the following scales
Aripiprazole in comparison with Haloperidol in were used: Visual analogue scale (VAS, Visual
the treatment of patients with substance use dis- Analogue Scale)48 and Substance craving
order comorbid with schizophrenia spec- scale (SCS).49
trum disorders. Drug safety was assessed by the development
of adverse events (AEs), serious adverse events
(SAEs), or adverse drug reactions (ADRs) in
Material and methods
patients, taking their symptoms, frequency, and
The group of patients with mental and behavioral severity into account. The Naranjo algorithm
disorders due to multiple drug use has been the (The Naranjo algorithm is one of the most widely
subject of this study. A total of 266 patients utilized causality assessment tools. This assess-
admitted to a drug treatment hospital were exam- ment is comprised of 10 questions concerning
ined. Of these, the study included 90 patients the implicated medication and reaction pheno-
with an established diagnosis of “Mental and type. Each answered question has an individual
behavioral disorders due to multiple drug use” score, which is then totaled to provide a final
(F19, according to ICD-10) comorbidly burdened score that is associated with one of four catego-
with schizophrenia spectrum disorders who ries of likelihood that the drug was associated
needed the inpatient psychopharmacological with the reaction (unlikely, possibly, probably, or
treatment. Inclusion criteria were: male gender; definitely)) was used for determining the likeli-
age between 20 and 50 years; diagnosis of schizo- hood of whether an adverse reaction was actually
phrenia spectrum disorder (F20, F21) which was due to the drug rather than the result of
previously established or revealed during the other factors.
study; informed consent to participate in the When AE, SAE, or ADR occurred, the phys-
study; informed consent to use the atypical anti- ician recorded his or her actions in the
psychotics (Aripiprazole, Quetiapine); informed documentation.
4 V. YU. SKRYABIN ET AL.

Table 1. Study design.

Visits Visit 0 Visit 1 Visit 2 Visit 3 Visit 4
Days of treatment Days 1–5 Day 5 Day 10 Day 15 Day 21
Procedures Screening Randomization Efficacy and safety evaluation Analysis of the results
Treatment of the substance Prescription of the medication
withdrawal syndrome
Establishing the diagnosis

Table 2. Minimal standard therapy of substance withdrawal syndrome.

Allowed medications (average daily dose) Prohibited medications
Potassium chloride þ Sodium bicarbonate þ Sodium chloride  800 mL Antipsychotics
Bromdihydrochlorphenylbenzodiazepine  4 mg Anticonvulsants
Hopantenic acid  750 mg Antidepressants
Tramadol  300 mg
Ketorolac  90 mg
Thiamine hydrochloride  100 mg
Pyridoxine hydrochloride  100 mg
Ethylmethylhydroxypyridine succinate  375 mg

Study design were positive (affective and behavioral disorders)

The total study duration was 21 days, which cor- and negative symptoms of the mental disorder.
responds to the standard course of inpatient Evaluation of the efficacy and safety of the pre-
treatment. Visit 0 corresponded to days 1–5 of scribed medications was carried out during the
inpatient treatment and included the procedures Visit 2 (day 10 of inpatient treatment), Visit 3
on screening and establishing the dual diagnosis (day 14 of inpatient treatment), and Visit 4 (day
of mental and behavioral disorders due to mul- 21 of inpatient treatment).
tiple drug use (F19) and paranoid schizophrenia In addition to the study drugs, patients
(F20), or schizotypal disorder (F21) (Table 1). received tranquilizers and hypnotics. The list of
The substance withdrawal syndrome was treated prohibited medications included any other psy-
during 4–5 days using the standard therapy chotropic drugs, including antipsychotics, antide-
(Hopantenic acid, the amide of D-pantoate and pressants, and anticonvulsants. Symptomatic
c-aminobutyric acid (GABA), is a central nervous therapy was conducted to correct somatic disor-
system depressant which is used as a pharma- ders: arterial hypertension or hypotension, tachy-
ceutical drug in the Russian Federation for a var- cardia, dyspeptic or other disorders.
iety of neurological, psychological and psychiatric During the study, quantification of the medica-
conditions.) (Table 2), which did not differ across tions used in the minimal standard therapy of
groups. On day 5 of inpatient treatment (i.e., substance withdrawal syndrome (Table 2) and
after the therapy of substance withdrawal syn- the post-acute withdrawal syndrome (Table 3)
drome), randomization (Visit 1) was carried out was conducted. During the statistical analysis, the
using a random number generator and the sealed volumes of medications received in the groups
envelope method. Each patient was assigned a were compared. No statistically significant differ-
two-digit serial number from 01 to 90 if he met ences were obtained.
the inclusion/exclusion criteria so that all patients
with a dual diagnosis were divided into three
Statistical analysis
groups (N ¼ 30) depending on the pharmaco-
logical agent. Patients in the first main group The study analyzed a sample of 90 observations.
were prescribed Aripiprazole (A) in a dose of up Each observation contained 15 variables. All varia-
to 20 mg daily. Patients of the second main group bles were quantitative. The data obtained were
were prescribed Quetiapine (Q) in a dose of up analyzed using descriptive comparative statistics.
to 600 mg daily. Patients of the third (control) The basic software for statistical analysis was IBM
group were prescribed Haloperidol (H) in a dose SPSS Statistics50 Ver. 22, Python Ver. 3.7, SciPy,
of up to 30 mg daily. The main targets of therapy NumPy, and Pandas libraries. Normal distribution
 JOURNAL OF ADDICTIVE DISEASES 5

Table 3. Minimal standard therapy of the post-acute withdrawal syndrome (PAWS).

Allowed medications (average daily dose) Prohibited medications
Aripiprazole  10 mg All other antipsychotics
Quetiapine  300 mg Antidepressants Anticonvulsants
Haloperidol  15 mg Nootropics
Bromdihydrochlorphenylbenzodiazepine – up to 4 mg
Tofisopam  150 mg
Tofisopam is an anxiolytic that is marketed in several European countries and indicated for the treatment of anxiety and alcohol
withdrawal.

was checked using the Shapiro-Wilk test, as well Study results

as a visual analysis of distribution histograms and Out of 90 patients included in the study, 22
quantile-quantile graphs. The Student’s paired t- patients were diagnosed with paranoid schizophre-
test was used to identify intragroup differences in nia (F20.014 – Episodic course with the progressive
continuous data with a normal distribution
development of negative symptoms in the intervals
(p > 0.05), and the Wilcoxon criterion was used
between psychotic episodes, and F20.03 – Episodic
for data that did not meet the normal distribution
remittent course with complete or virtually com-
law (p < 0.05). For the intergroup comparisons of
plete remissions between psychotic episodes,
continuous data with a normal distribution, the
according to ICD-10); 68 patients were diagnosed
Student’s unpaired t-test was used. When the data
with the schizotypal disorder (F21.1 – Latent
did not meet the normal distribution law, the one-
schizophrenia; F21.3 – Pseudoneurotic schizophre-
sample Wilcoxon test was used.
nia; F21.4 – Pseudopsychopathic schizophrenia;
Correlation analysis of data with normal distri-
F21.5 – «Symptom-depleted» schizophrenia; F21.8
bution was carried out using the Pearson criter-
– Schizotypal personality disorder). Despite differ-
ion. For the data that did not meet the law of
normal distribution, a nonparametric Spearman ent ICD-10 diagnostic codes, the group was con-
correlation coefficient was used. The correlations sidered in total volume, since the number of
were considered weak at 0.5  h > 0.2; moderate observations with each variant of the schizophrenic
at 0.7  h > 0.5, and strong at 0.9  h > 0.7. process was limited and the clinical picture of all
ANOVA dispersion analysis was also used to patients was very similar. In all patients, the mental
estimate the mean values in the three independ- disorder was characterized by a relatively favorable,
ent groups with a normal distribution. slow-progressive course, the clinical picture was
Due to the problem of multiple comparisons, dominated by different variants of depressive and
or multiple testing problem (3 groups), the fol- subthreshold depressive disorders, and the pro-
lowing formula was used to calculate the p-value: ductive symptoms included overvalued and para-
1  0.951/3 ¼ 0.016952. noid ideas that did not reach the level of delusion.
Parameters given in the tables have the following Deficit symptoms were manifested in the form of
designations: mean – mean value, std – standard autism, isolation, emotional exhaustion, tangential-
(root-mean-square, RMS) deviation, count – a volume ity, distractible speech, and alogia.
of the analyzed subgroup, p – the significance level. Out of a total sample, 54 patients (60%) had a
As primary efficacy indicators, data on the preexisting psychiatric diagnosis and underwent
dynamics of symptoms according to BPRS and follow-up. Meanwhile, 36 patients (40%) had
PANSS scales were used. The efficacy of the never been admitted to a psychiatrist before
investigational drugs was considered to be posi- actual hospitalization, although clinical evidence
tive when achieving the statistical reliability with suggested the presence of mental disorder comor-
the comparison drug by Visit 4. bid with the substance use disorder. The
Other criteria of the drug efficacy: the number of CONSORT Flow Diagram (Figure 1) suggests
patients (%) with adverse events; the number of that comorbid mental disorders are quite com-
patients (%) who completed the study; and the num- mon among patients with substance use disorders
ber of patients (%) who needed the additional ther- (they occur almost in 34% of cases), but in a
apy were referred to the secondary efficacy criteria. large number of such patients (in our study – in
6 V. YU. SKRYABIN ET AL.

Figure 1. Distribution of study participants.

40% of the screened patients, or 13.5% of those prevalence of drug misuse (62%); 7) predominance
examined for multiple drug use disorder) the of psychopathological symptoms in the structure of
mental disorder remains unrecognized. This leads withdrawal syndrome (subthreshold depressive
to ineffective therapies, which in turn results in mood, mood swings, self-incriminating ideas and
frequent relapses, rapid social disadaptation, and suspiciousness reaching the paranoia level  68%);
extremely early disability. 8) predominance of the ideational component in
the structure of craving (52%); 9) the pattern of
Peculiarities of the clinical picture of substance drug use is chaotic, with more than 2 substances
use disorder comorbid with the (66.7%); the most frequent combinations of sub-
schizophrenic process stances in patients with a dual diagnosis are combi-
nations of psychoactive substances with
Patients with a dual diagnosis are characterized by
cholinolytics, such as alcohol, psychostimulants,
the following clinical and dynamic peculiarities of
cholinolytics (22.2%), alcohol, opioids, cholinolytics
the clinical picture: 1) early social disadaptation, as
(15.2%), and psychostimulants and cholinolytics
evidenced by low numbers of employed individuals
(12.4%). Opioids were the most commonly used
(20%) and high numbers of single and unmarried
psychoactive substances among the patients from
persons (80%); 2) trend to develop “hospitalism,”
the main groups (52 patients, 57.8%), followed by
possibly associated with frequent relapses and poor
alcohol (21 patients, 23.3%), and synthetic cathi-
quality of remissions, as evidenced by high hospital-
nones (17 individuals, 18.9%). In the control group,
ization rates during one year (42%); 3) the develop-
in most cases patients used opioids (heroin, street
ment of substance use disorder at an early age:
methadone) (133 patients, 75.6%) and psychostimu-
21.2 ± 1.9 years; 4) the most frequent motivation for
lants (43 individuals, 24.4%).
initiation of substance use is the so-called
“experiment” (according to patients, “the scientific
method of use,” i.e. not for euphoria, but to study
Analysis of dependent variables, intragroup
the effect of psychoactive substance on the brain 
comparisons
39.9%), or “the desire to calm down or raise the
mood” (i.e., for the correction of mental state  The analysis of the dependent variables according
35.7%); 5) unusual motivation to involve in the use to the BPRS and PANSS scales has revealed sig-
of psychoactive substances – to “join the company” nificant differences in the dynamics of therapy in
(7.1%); 6) predominance of highly progressive three groups when comparing Visit 1 and Visit 4
course of substance use disorder (62%), the (Table 4).
 JOURNAL OF ADDICTIVE DISEASES 7

Table 4. Intragroup dynamics by the BPRS and PANSS scales.

Group Scale, Visits mean ± std p-value Criterion used to calculate h-value
A BPRS, V1 67.86 ± 4.37 0.0001 Wilcoxon signed-rank test
BPRS, V4 20.90 ± 9.12
PANSS P, V1 20.86 ± 2.15 0.0001 Wilcoxon signed-rank test
PANSS P, V4 2.67 ± 2.52
PANSS , V1 33.52 ± 3.63 0.0001 Paired Student’s t-test
PANSS , V4 5.76 ± 3.94
Q BPRS, V1 68.40 ± 4.79 0.0001 Paired Student’s t-test
BPRS, V4 22.80 ± 9.77
PANSS P, V1 20.20 ± 3.97 0.0001 Paired Student’s t-test
PANSS P, V4 3.35 ± 3.00
PANSS , V1 35.10 ± 2.75 0.0001 Paired Student’s t-test
PANSS , V4 7.63 ± 5.34
H BPRS, V1 69.58 ± 3.52 0.0001 Paired Student’s t-test
BPRS, V4 27.89 ± 8.94
PANSS P, V1 19.74 ± 3.38 0.0001 Paired Student’s t-test
PANSS P, V4 7.42 ± 2.89
PANSS , V1 34.47 ± 4.71 0.0001 Paired Student’s t-test
PANSS , V4 12.84 ± 2.89
Note: A – main group 1, received Aripiprazole; Q – main group 2, received Quetiapine; H – control group, received
Haloperidol; V1 – visit 1; V4 – visit 4.

Table 5. Intragroup dynamics by the VAS and SCS scales.

Group Scale, Visits mean ± std p-value Criterion used to calculate h-value
A VAS, V1 53.10 ± 11.45 0.0001 Paired Student’s t-test
VAS, V4 12.86 ± 5.38
SCS, V1 21.81 ± 3.22 0.0001 Paired Student’s t-test
SCS, V4 3.71 ± 2.53
Q VAS, V1 56.75 ± 10.67 0.0001 Paired Student’s t-test
VAS, V4 19.75 ± 8.50
SCS, V1 21.30 ± 2.81 0.0001 Paired Student’s t-test
SCS, V4 6.40 ± 3.42

VAS, V1 80.53 ± 7.97 0.0001 Wilcoxon signed-rank test
VAS, V4 39.74 ± 7.35
SCS, V1 22.47 ± 3.19 0.0001 Wilcoxon signed-rank test
SCS, V4 11.89 ± 1.10
Note: A – main group 1, received Aripiprazole; Q – main group 2, received Quetiapine; H – control group, received Haloperidol; V1 – visit 1; V4 – visit 4.

Along with the positive dynamics of the differences between groups A and H were
schizophrenia spectrum disorders, the reduction obtained by Visit 4 on the PANSS scale of gen-
of symptoms of substance use disorders (in par- eral psychopathology (O): mean
¼ 12.84 ± 2.89;
ticular, craving) was also noted (Table 5). meanff ¼ 5.76 ± 3.94; positive symptoms (P):
The results obtained (Tables 4 and 5) allow us mean
¼ 7.42 ± 2.89; meanff ¼ 2.67 ± 2.52. In
to draw an unambiguous conclusion about the addition, by Visit 4, reliable differences between
effectiveness of antipsychotics in the treatment of the groups according to the BPRS scale were
patients with a dual diagnosis. However, the obtained: mean
¼ 27.89 ± 8.94; meanff
information about the specificity of each medica- ¼ 20.9 ± 9.12.
tion used, which can be seen in intergroup com- Significant differences on the substance craving
parisons, is of the greatest practical interest. scales were determined earlier than the reduction
of positive and specific negative symptoms: by
Visit 2 (SCS) or Visit 3 (VAS). Intergroup com-
Analysis of independent variables, intergroup
parison shows that Aripiprazole is more effective
comparisons
than Haloperidol in reducing craving (SCS,
At the stage of screening (V0) and randomization VAS): mean SCSff 10.71 ± 1.19, mean SCS

(V1), the groups did not differ from each other 17.79 ± 1.90; mean VASff 31.19 ± 10.24, mean
in terms of the scales. The statistically significant VAS
53.16 ± 8.37 (Table 7).
differences between the groups were revealed by This fact may be useful in determining the
the end of the study (V4) (Table 6). Significant duration of therapy with antipsychotic drugs.
8 V. YU. SKRYABIN ET AL.

Table 6. Aripiprazole in comparison with Haloperidol: an analysis of intergroup differences on the

BPRS and PANSS scales.
Group ff, Group
,
Scale, Visit mean ± std mean ± std p-value Criterion used to calculate h-value
PANSS_O, V1 33.52 ± 3.63 34.47 ± 4.71 0.4767 Unpaired Student’s t-test
PANSS_ O, V4 5.76 ± 3.94 12.84 ± 2.89 0.0001 Mann–Whitney U test
PANSS_P, V1 20.86 ± 2.15 19.74 ± 3.38 0.1617 Mann–Whitney U test
PANSS_P, V4 2.67 ± 2.52 7.42 ± 2.89 0.0001 Mann–Whitney U test
BPRS, V1 67.86 ± 4.37 69.58 ± 3.52 0.1810 Unpaired Student’s t-test
BPRS, V4 20.90 ± 9.12 27.89 ± 8.94 0.0097 Mann–Whitney U test
Note: A – main group 1, received Aripiprazole; H – control group, received Haloperidol; V1 – visit 1; V4 – visit 4.

Table 7. Aripiprazole in comparison with Haloperidol: an analysis of intergroup differences on the VAS and
SCS scales.
Group ff,
Scale, Visit mean ± std Group
, mean ± std p-value Criterion used to calculate h-value
SCS, V1 21.81 ± 3.22 22.47 ± 3.19 0.2223 Mann–Whitney U test
SCS, V2 10.71 ± 1.19 17.79 ± 1.90 0.0001 Mann–Whitney U test
SCS, V4 3.71 ± 2.53 11.89 ± 1.10 0.0001 Mann–Whitney U test
VAS, V1 53.10 ± 11.45 67.63 ± 9.33 0.1850 Mann–Whitney U test
VAS, V3 31.19 ± 10.24 53.16 ± 8.37 0.0001 Mann–Whitney U test
VAS, V4 12.86 ± 5.38 39.74 ± 7.35 0.0001 Mann–Whitney U test
Note: A – main group 1, received Aripiprazole; H – control group, received Haloperidol; V1 – visit 1; V2 – visit 2; V3 – visit 3;
V4 – visit 4.

Table 8. Quetiapine in comparison with Haloperidol: an analysis of intergroup differences on the BPRS
and PANSS scales.
Group Q, Group
,
Scale, Visit mean ± std mean ± std p-value Criterion used to calculate h-value
PANSS_O, V1 35.10 ± 2.75 34.47 ± 4.71 0.6127 Unpaired Student’s t-test
PANSS_ O, V4 7.63 ± 5.34 12.84 ± 2.89 0.0029 Mann–Whitney U test
PANSS_P, V1 20.20 ± 3.97 19.74 ± 3.38 0.4215 Mann–Whitney U test
PANSS_P, V4 3.35 ± 3.00 7.42 ± 2.89 0.0001 Mann–Whitney U test
BPRS, V1 68.40 ± 4.79 69.58 ± 3.52 0.3890 Unpaired Student’s t-test
BPRS, V4 22.80 ± 9.77 27.89 ± 8.94 0.0983 Unpaired Student’s t-test
Note: Q – main group 2, received Quetiapine; H – control group, received Haloperidol; V1 – visit 1; V4 – visit 4.

Table 9. Quetiapine in comparison with Haloperidol: an analysis of intergroup differences on the

SCS and VAS scales.
Group Q, Group
,
Scale, Visit mean ± std mean ± std p-value Criterion used to calculate h-value
SCS, V1 21.30 ± 2.81 22.47 ± 3.19 0.0910 Mann–Whitney U test
SCS, V4 6.40 ± 3.42 17.79 ± 1.90 0.0001 Mann–Whitney U test
VAS, V1 56.75 ± 10.67 67.63 ± 9.33 0.6760 Unpaired Student’s t-test
VAS, V4 19.75 ± 8.50 39.74 ± 7.35 0.0001 Mann–Whitney U test
Note: Q – main group 2, received Quetiapine; H – control group, received Haloperidol; V1 – visit 1; V4 – visit 4.

An intergroup comparison of groups Q and H An intergroup comparison of groups A and Q

revealed differing results. On the PANSS scale, showed that the two medications were equally effect-
significant differences were obtained between the ive with respect to the positive symptoms of the
groups by Visit 4: on the scale of general psycho- schizophrenic process (lack of reliable statistical differ-
pathology () mean
¼ 12.84 ± 2.89; meanQ ¼ ences between groups on PANSS and BPRS scales).
7.36 ± 5.34; positive symptoms (P) mean
¼ However, a more pronounced statistically significant
7.42 ± 2.89; meanff ¼ 3.35 ± 3.00. No significant effectiveness of Aripiprazole compared to Quetiapine
differences were obtained on the BPRS scale with respect to craving was revealed (mean SCSff
(Table 8). On the substance craving scales (SCS, 3.71 ± 2.53, mean SCSQ 6.40 ± 3.42; mean VASff
VAS), significant differences were also deter- 12.86 ± 5.38, mean VASQ 19.75 ± 8.50) (Table 10).
mined by Visit 4: mean SCSQ 6.40 ± 3.42, mean With regard to the peculiarities of clinical
SCS
17.79 ± 1.90; mean VASQ 19.75 ± 8.50, action, Aripiprazole was most effective in reliev-
mean VAS
39.74 ± 7.35 (Table 9). ing ideational disorders (overvalued experiences,
 JOURNAL OF ADDICTIVE DISEASES 9

Table 10. Aripiprazole in comparison with Quetiapine: an analysis of intergroup differences on the BPRS, PANSS,
VAS, and SCS scales.
Scale, Visit Group ff, mean ± std Group Q, mean ± std p-value Criterion used to calculate h-value
PANSS_O, V1 33.52 ± 3.63 35.10 ± 2.75 0.1265 Unpaired Student’s t-test
PANSS_ O, V4 5.76 ± 3.94 7.63 ± 5.34 0.0383 Mann–Whitney U test
PANSS_P, V1 20.86 ± 2.15 20.20 ± 3.97 0.2599 Mann–Whitney U test
PANSS_P, V4 2.67 ± 2.52 3.35 ± 3.00 0.2467 Mann–Whitney U test
BPRS, V1 67.86 ± 4.37 68.40 ± 4.79 0.7067 Unpaired Student’s t-test
BPRS, V 4 20.90 ± 9.12 22.80 ± 9.77 0.2691 Mann–Whitney U test
SCS, V1 21.81 ± 3.22 21.30 ± 2.81 0.2762 Mann–Whitney U test
SCS, V4 3.71 ± 2.53 6.40 ± 3.42 0.0024 Mann–Whitney U test
VAS, V1 53.10 ± 11.45 56.75 ± 10.67 0.2976 Unpaired Student’s t-test
VAS, V4 12.86 ± 5.38 19.75 ± 8.50 0.0034 Unpaired Student’s t-test
Note: A – main group 1, received Aripiprazole; Q – main group 2, received Quetiapine; V1 – visit 1; V4 – visit 4.

Table 11. Correlation analysis between the measures of BPRS, p < 0.01), positive symptoms (P) rs ¼ 0.5697,
PANSS, SCS, and VAS scales. (95% CI 0.583; 0.829), n ¼ 90, p < 0.01)
VAS, V1 VAS, V4 SCS, V4
(Table 11).
BPRS, V1 0.8153
PANSS_ O, V4 0.5647 0.5823 The obtained strong and moderate correlation
PANSS_ N, V4 0.6316 0.5744 coefficients allow us to conclude that psycho-
PANSS_P, V4 0.5697 0.5019
Note: V1 – Visit 1; V4 – Visit 4.
pathological symptoms of mental disorder and
Pearson’s chi-squared test to calculate h. substance use disorder are in linear dependence:
Spearman rank correlation coefficient to calculate h.
the increase of mental disorder manifestations
paranoia, decreased critical abilities, etc.) in the leads to the increase of craving, and their
structure of craving; Quetiapine was most effect- decrease leads to the decrease of craving.
ive in relieving the affective component of crav-
ing (depressive mood, anxiety, the intensity of Safety profile
affect, etc.); Haloperidol was most effective in Adverse reactions identified were short-term, did
relieving behavioral disorders (aggression, psy- not require cancelation of medications or pre-
chopathic behavior, etc.) and the ideational com- scription of additional treatment, were identified
ponent of craving. while questioning patients only, and passed inde-
pendently. The causal link with the use of medi-
Correlation analysis cation was doubtful in all but one manifestation
(tremor), and clinical manifestations did not go
Correlation analysis was carried out in the gen-
beyond the priority manifestations of the with-
eral sample to demonstrate the close relationship
drawal syndrome and post-acute withdrawal syn-
between the signs of mental and substance use
drome (Table 12).
disorder. Linear correlations between the PANSS,
Unfavorable adverse reactions were revealed in
BPRS, VAS, and SCS scales were identified.
16.7% of patients taking Aripiprazole. In the
Linear dependencies were found at the visit 1
group of patients who took Quetiapine, adverse
between VAS and BPRS scales (rs ¼ 0.8153,
reactions occurred in 26.4% of patients. In the
(95% CI 0.708; 0.886), n ¼ 90, p < 0.01), and on
group of patients who were prescribed
the visit 4 between SCS and PANSS scales (gen-
Haloperidol, adverse reactions occurred in 56.7%
eral psychopathology (O) (rs ¼ 0.5823, (95% CI
of patients. The number of patients who com-
0.712; 0.836), n ¼ 90, p < 0.01), negative symp-
pleted the study was as follows: Aripiprazole 
toms (N) (rs ¼ 0.5744, (95% CI 0.620; 0.860), 83.3%, Quetiapine  73.6%, Haloperidol
n ¼ 90, p < 0.01), positive symptoms (P) rs ¼  43.3%.
0.5019, (95% CI 0.321; 0.661), n ¼ 90, p < 0.01),
between VAS and PANSS scales (general psycho-
pathology (O) (rs ¼ 0.5647, (95% CI 0.369; Conclusion
0.721), n ¼ 90, p < 0.01), negative symptoms (N) The results of a blind randomized comparative
(rs ¼ 0.6316, (95% CI 0.4512; 0.7630), n ¼ 90, study of atypical antipsychotics in the treatment
10 V. YU. SKRYABIN ET AL.

Table 12. Adverse reactions observed.

Aripiprazole Quetiapine Haloperidol
Clinical manifestations Number of patients (%) Number of patients (%) Number of patients (%) Causal link
Tremor 1 (3.3%) 11 (36.6%) Definite
Drowsiness 2 (6.6%) 4 (13.3%) 3 (10%) Doubtful
Increase in anxiety level 1 (3.3%) Doubtful
Headache 1 (3.3%) 1 (3.3%) Doubtful
Blood pressure decrease 1 (3.3%) Doubtful
Dizziness 1 (3.3%) Doubtful
Xerostomia 1 (3.3%) 2 (6.6%) Doubtful

of patients suffering from substance use disorder equally effective for schizophrenic symptoms (no
and schizophrenia spectrum disorder showed significant statistical differences between the
the following. groups on the PANSS and BPRS scales), but
Comorbid schizophrenia spectrum disorders Aripirazole was more effective for substance use
(mainly, slow-progressive forms of schizophrenia) disorders in comparison with Quetiapine (signifi-
are common in patients with substance use disor- cant differences on the SCS and VAS scales).
ders. In our study, the proportion of patients The efficacy of atypical antipsychotics in rela-
with a dual diagnosis was 34%. In slightly less tion to schizophrenic manifestations is evident by
than half of these patients (40%), mental disor- the end of week 3 of treatment (Visit 4), and in
ders remained unrecognized. This can be attrib- relation to manifestations of craving – by the end
uted to the fact that mental disorder in such of week 2 (Visits 2, 3). These data can be used to
patients is erased, the clinical picture is domi- determine the duration of antipsychotic therapy.
nated by depressive and subthreshold depressive The obtained strong and moderate correlation
disorders, overvalued paranoid ideas that do not coefficients suggest that psychopathological symp-
reach the level of delusion, which are very similar toms of mental and substance use disorders are
to the clinical manifestations of substance use in linear dependence: the increase of mental dis-
disorders and can be considered in the structure order manifestations leads to the increase of crav-
of craving, withdrawal syndrome, or mental deg- ing, and their decrease leads to the decrease of
radation. Deficit symptoms (autism, increasing craving. In our opinion, the obtained result testi-
isolation, emotional coldness) and specific fies to the syndromological equivalence of psy-
thought disorders (tangentiality, distractible chopathological manifestations of mental and
speech, alogia, etc.) are often underdiagnosed. substance use disorders, in particular, craving.
This leads to ineffective therapy regimens, which From this, we can conclude that the medications
in turn results in frequent relapses, rapid social used to control the manifestations of mental dis-
disadaptation, and extremely early disability of order are effective in the management of craving.
these patients. This confirms the statement that in cases of sub-
Significant intragroup differences obtained on stance use disorder comorbid with a mental dis-
all scales in all groups allow us to draw a clear order treatment tactics should be identical to the
conclusion about the effectiveness of antipsy- treatment tactics for the endogenous disease.
chotics, both atypical and traditional, in the treat-
ment of patients with a dual diagnosis.
The obtained intergroup differences between
atypical antipsychotics (Aripiprazole, Quetiapine) Declaration of interest
and traditional antipsychotics (Haloperidol) on The authors declare that there is no conflict of
the PANSS, BPRS, VAS, and SCS scales allow us interest regarding the publication of this article.
to conclude that atypical antipsychotics are more
effective in both mental and substance
use disorders.
Intergroup comparison of Aripiprazole and Funding
Quetiapine showed that the two medications were The research received no external funding.
 JOURNAL OF ADDICTIVE DISEASES 11

Ethics approval and consent to participate 2015;225(3):395–401. doi:10.1016/j.psychres.2014.12.

006.
Written informed consent was obtained from 7. Swendsen J, Conway KP, Degenhardt L, Glantz M, Jin
each subject following a detailed explanation of R, Merikangas KR, Sampson N, Kessler RC. Mental
the objectives and protocol of the study, which disorders as risk factors for substance use, abuse and
was conducted in accordance with the ethical dependence: results from the 10-year follow-up of the
national comorbidity survey. Addiction. 2010;105(6):
principles stated in the Declaration of Helsinki
1117–28. doi:10.1111/j.1360-0443.2010.02902.x.
and approved by the Ethics Committee of the 8. Bhalla IP, Stefanovics EA, Rosenheck RA. Clinical epi-
Moscow Research and Practical Center on demiology of single versus multiple substance use dis-
Addictions of the Moscow Department orders: polysubstance use disorder. Med Care. 2017;
of Healthcare. 55(Suppl 9 Suppl 2):S24–S32. doi:10.1097/MLR.
0000000000000731.
9. Dixon L. Dual diagnosis of substance abuse in schizo-
Authors’ contributions phrenia: prevalence and impact on outcomes.
Schizophr Res. 1999;35(Suppl):S93–S100. doi:10.1016/
All authors made substantial contributions to
S0920-9964(98)00161-3.
conception and design, acquisition of data, and 10. Linszen DH, Dingemans PM, Lenior ME. Cannabis
analysis and interpretation of data; all authors abuse and the course of recent-onset schizophrenic
participated in drafting the article and revising it disorders. Arch Gen Psychiatry. 1994;51(4):273–9. doi:
critically for important intellectual content; and 10.1001/archpsyc.1994.03950040017002.
all authors gave final approval of the version to 11. Libuy N, de Angel V, Ib
an ~ez C, Murray RM, Mundt
AP. The relative prevalence of schizophrenia among
be submitted.
cannabis and cocaine users attending addiction serv-
ices. Schizophr Res. 2018;194:13–7. doi:10.1016/j.
ORCID schres.2017.04.010.
12. Chiappelli J, Chen S, Hackman A, Hong LE. Evidence
V. Yu. Skryabin http://orcid.org/0000-0002-4942-8556 for differential opioid use disorder in schizophrenia in
an addiction treatment population. Schizophr Res.
References 2018;194:26–31. doi:10.1016/j.schres.2017.05.004.
13. Bramness JG, Gundersen OH, Guterstam J, Rognli
1. Scheller-Gilkey G, Moynes K, Cooper I, Kant C, EB, Konstenius M, Løberg EM, Medhus S, Tanum L,
Miller AH. Early life stress and PTSD symptoms in Franck J. Amphetamine-induced psychosis-a separate
patients with comorbid schizophrenia and substance diagnostic entity or primary psychosis triggered in the
abuse. Schizophr Res. 2004;69(2–3):167–74. doi:10. vulnerable? BMC Psychiatry. 2012;12:221. doi:10.1186/
1016/S0920-9964(03)00188-9. 1471-244X-12-221.
2. Bokhan NA, Semke VYA. [Co-morbidity in addiction 14. Green AI, Khokhar JY. Addiction and schizophrenia:
psychiatry]. Tomsk: Publishing House of Tomsk a translational perspective. Schizophr Res. 2018;194:
University; 2009. 510 p. [Last accessed March 23, 1–3. doi:10.1016/j.schres.2017.10.008.
2021] http://www.mental-health.ru/files/edu/mono- 15. European Monitoring Centre for Drugs and Drug
graph/self/007.pdf. [Article in Russian] Addiction. European Drug Report. Luxembourg:
3. Moggi F. [Epidemiology, etiology and treatment of Trends and Developments, Publications Office of the
patients with psychosis and co-morbid substance use European Union; 2019. ISBN 978-92-9497-445-7. doi:
disorder]. Ther Umsch. 2018;75(1):37–43. doi:10.1024/ 10.2810/576732.
0040-5930/a000964. [Article in German] 16. Kirzhanova VV, Grigorova NI, Kirzhanov VN,
4. Janoutov
a J, Jan
ackov
a P, Ser
y O, Zeman T, Ambroz Sidoryuk OV. The basic parameters of activity of nar-
P, Kovalov
a M, Varechov
a K, Hos
ak L, Jir
ık V, cological service in the Russian Federation in 2015-
Janout V. Epidemiology and risk factors of schizo- 2016. A statistical compendium. Moscow: The Serbsky
phrenia. Neuro Endocrinol Lett. 2016;37(1):1–8. State Scientific Center for Social and Forensic
5. Green AI, Tohen MF, Hamer RM, Strakowski SM, Psychiatry; 2017. 183 p. [Article in Russian]
Lieberman JA, Glick I, Clark WS, HGDH Research 17. Crockford D, Addington D. Canadian schizophrenia
Group. First episode schizophrenia-related psychosis guidelines: schizophrenia and other psychotic disor-
and substance use disorders: acute response to olanza- ders with coexisting substance use disorders. Can J
pine and haloperidol. Schizophr Res. 2004;66(2–3): Psychiatry. 2017;62(9):624–34. doi:10.1177/
125–35. doi:10.1016/j.schres.2003.08.001. 0706743717720196.
6. Kerner B. Comorbid substance use disorders in 18. Khokhar JY, Dwiel LL, Henricks AM, Doucette WT,
schizophrenia: a latent class approach. Psychiatry Res. Green AI. The link between schizophrenia and
12 V. YU. SKRYABIN ET AL.

substance use disorder: a unifying hypothesis. quetiapine treatment for cannabis dependence. Am J
Schizophr Res. 2018;194:78–85. doi:10.1016/j.schres. Drug Alcohol Abuse. 2014;40(4):280–4. doi:10.3109/
2017.04.016. 00952990.2014.884102.
19. Ipser JC, Wilson D, Akindipe TO, Sager C, Stein DJ. 30. Awad AG. The neurobiology of comorbid drug abuse
Pharmacotherapy for anxiety and comorbid alcohol in schizophrenia and psychotic disorders. In: V. R.
use disorders. Cochrane Database Syst Rev. 2015;1: Preedy (Ed.), Neuropathology of drug addictions and
CD007505. doi:10.1002/14651858.CD007505.pub2. substance misuse. Academic Press, London, 2016 p.
20. Unglaub W, Kandel M, Zenner D, Wodarz N, Klein 82–8. doi:10.1016/b978-0-12-800213-1.00008-0.
H. [Neuroleptic therapy of comorbid narcotic depend- 31. Martinotti G, Orsolini L, Fornaro M, Vecchiotti R, De
ent patients in ambulatory methadone maintenance]. Berardis D, Iasevoli F, Torrens M, Di Giannantonio
Psychiatr Prax. 2003;30(Suppl 2):S121–4. [Article in M. Aripiprazole for relapse prevention and craving in
German]
alcohol use disorder: current evidence and future per-
21. Gouzoulis-Mayfrank E. [Dual diagnosis psychosis and
spectives. Expert Opin Investig Drugs. 2016;25(6):
substance use disorders: theoretical foundations and
719–28. doi:10.1080/13543784.2016.1175431.
treatment]. Z Kinder Jugendpsychiatr Psychother.
32. Martinotti G, Di Nicola M, Di Giannantonio M,
2008;36(4):245–53. doi:10.1024/1422-4917.36.4.245.
Janiri L. Aripiprazole in the treatment of patients
[Article in German]
22. Potvin S, Stip E, Lipp O, Elie R, Mancini-Mari€e A, with alcohol dependence: a double-blind, comparison
Demers MF, Roy MA, Bouchard RH, Gendron A. trial vs. naltrexone. J Psychopharmacol. 2009;23(2):
Quetiapine in patients with comorbid schizophrenia- 123–9. doi:10.1177/0269881108089596.
spectrum and substance use disorders: an open-label 33. Indave BI, Minozzi S, Pani PP, Amato L.
trial. Curr Med Res Opin. 2006;22(7):1277–85. doi:10. Antipsychotic medications for cocaine dependence.
1185/030079906X112561. Cochrane Database Syst Rev. 2016;3:CD006306. doi:
23. Cuomo I, Kotzalidis GD, de Persis S, Piacentino D, 10.1002/14651858.CD006306.pub3.
Perrini F, Amici E, De Filippis S. Head-to-head com- 34. Coffin PO, Santos GM, Das M, Santos DM, Huffaker
parison of 1-year aripiprazole long-acting injectable S, Matheson T, Gasper J, Vittinghoff E, Colfax GN.
(LAI) versus paliperidone LAI in comorbid psychosis Aripiprazole for the treatment of methamphetamine
and substance use disorder: impact on clinical status, dependence: a randomized, double-blind, placebo-
substance craving, and quality of life. Neuropsychiatr controlled trial. Addiction. 2013;108(4):751–61. doi:10.
Dis Treat. 2018;14:1645–56. doi:10.2147/NDT. 1111/add.12073.
S171002. 35. Samaha AN. Can antipsychotic treatment contribute
24. Hanley MJ, Kenna GA. Quetiapine: treatment for sub- to drug addiction in schizophrenia? Prog
stance abuse and drug of abuse. Am J Health Syst Neuropsychopharmacol Biol Psychiatry. 2014;52:9–16.
Pharm. 2008;65(7):611–8. doi:10.2146/ajhp070112. doi:10.1016/j.pnpbp.2013.06.008.
25. Brunetti M, Di TL, Dezi S, Pozzi G, Grandinetti P. 36. Brown ES, Davila D, Nakamura A, Carmody TJ, Rush
Martinotti G. Aripiprazole, alcohol and substance AJ, Lo A, Holmes T, Adinoff B, Caetano R, Swann
abuse: a review. Eur Rev Med Pharmacol Sci. 2012; AC, Sunderajan P, et al. A randomized, double-blind,
16(10):1346–54. placebo-controlled trial of quetiapine in patients with
26. Bruno A, Romeo VM, Pandolfo G, Scimeca G,
bipolar disorder, mixed or depressed phase, and alco-
Zoccali RA, Muscatello MRA. Aripiprazole plus topir-
hol dependence. Alcohol Clin Exp Res. 2014;38(7):
amate in opioid-dependent patients with schizoaffec-
2113–8. doi:10.1111/acer.12445.
tive disorder: an 8-week, open-label, uncontrolled,
37. Carney A. Efficacy of quetiapine off-label uses: data
preliminary study. Subst Abus. 2014;35(2):119–21.
synthesis. J Psychosoc Nurs Ment Health Serv. 2013;
doi:10.1080/08897077.2013.814615.
51(8):11–8. doi:10.3928/02793695-20130709-01.
27. Beresford T, Buchanan J, Thumm EB, Emrick C,
38. Janicak PG, Rado JT. Quetiapine monotherapy for
Weitzenkamp D, Ronan PJ. Late reduction of cocaine
cravings in a randomized, double-blind trial of aripi- bipolar depression. Expert Opin Pharmacother. 2011;
prazole vs perphenazine in schizophrenia and comor- 12(10):1643–51. doi: 10.1517/14656566.2011.585461.
bid cocaine dependence. J Clin Psychopharmacol. 39. Ghaemi SN, Ko JY, Goodwin FK. "Cade’s disease" and
2017;37(6):657–63. doi:10.1097/JCP. beyond: misdiagnosis, antidepressant use, and a pro-
0000000000000789. posed definition for bipolar spectrum disorder. Can J
28. Monnelly EP, Ciraulo DA, Knapp C, LoCastro J, Psychiatry. 2002;47(2):125–34. doi:10.1177/
Sepulveda I. Quetiapine for treatment of alcohol 070674370204700202.
dependence. J Clin Psychopharmacol. 2004;24(5): 40. Gao K, Sheehan DV, Calabrese JR. Atypical antipsy-
532–5. doi:10.1097/01.jcp.0000138763.23482.2a. chotics in primary generalized anxiety disorder or
29. Mariani JJ, Pavlicova M, Mamczur AK, Bisaga A, comorbid with mood disorders. Expert Rev
Nunes EV, Levin FR. Open-label pilot study of Neurother. 2009;9(8):1147–58. doi:10.1586/ern.09.37.
 JOURNAL OF ADDICTIVE DISEASES 13

41. Maksimov VG. [Quetiapine and its place in the treat- Index. J Nerv Ment Dis. 1980;168(1):26–33. doi:10.
ment of various diseases with atypical antipsychotics]. 1097/00005053-198001000-00006.
J Trudnyj Pacient. 2009;9:42–5. [Article in Russian] 46. Overall E, Gorham D. The Brief Psychiatric Rating
42. Kane JM, Carson WH, Saha AR, McQuade RD, Scale (BPRS): recent developments in ascertainment
Ingenito GG, Zimbroff DL, Ali MW. Efficacy and and scaling. Psychopharmacol Bull. 1988;1(24):97–9.
safety of aripiprazole and haloperidol versus placebo 47. Lachar D, Bailley SE, Rhoades HM, Varner RV. Use
in patients with schizophrenia and shizoaffective dis- of BPRS - a percent change scores to identify signifi-
order. J Clin Psychiatry. 2002;63(9):763–71. doi:10. cant clinical improvement: accuracy of treatment
4088/JCP.v63n0903.
response classification in acute psychiatric inpatients.
43. Pinkofsky HB, Hahn AM, Campbell FA, Rueda J,
Psychiatry Res. 1999;89(3):259–68. doi:10.1016/S0165-
Daley DC, Douaihy AB. Reduction of opioid-with-
drawal symptoms with quetiapine. J Clin Psychiatry. 1781(99)00114-6.
2005;66(10):1285–8. doi:10.4088/jcp.v66n1011. 48. Huskisson E. Measurement of pain. Lancet. 1974;
44. Saffar SP, Schultz S, Amdt S, Soundy T, Petty F. 304(7889):1127–31. doi:10.1016/S0140-6736(74)90884-8.
Long-term adjunctive quetiapine may reduce sub- 49. Ivanets NN, Vinnikova MA. [Diagnostic criteria for
stance use - a preliminary retrospective study. S D the severity of pathological drug addiction]. Zhurnal
Med. 2007;60(11):437,439–41. 443 passim. Nevropatologii i Psixiatrii im. S.S.Korsakova. 2001;
45. McLellan AT, Luborsky L, Woody GE, O’Brien CP. 8(101):4–8. [Article in Russian]
An improved diagnostic evaluation instrument for 50. IBM SPSS Statistics, Ver. 22. Available from https://
substance abuse patients. The Addiction Severity www.ibm.com/products/spss-statistics