Adres do korespondencji:
Fabiana Ventura,
Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugalia,
e-mail: fabi.ventura4@gmail.com
Fabiana Ventura, Mariana Jesus, César Mendes, Carla Silva
Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugalia
Schizophrenia and substance use disorder: a retrospective study of a dual diagnosis patients cohort
Abstract
Introduction: Approximately 47% of patients with Schizophrenia have criteria for a dual diagnosis. The con- sumption of illicit substances, particularly cannabis, is quite prevalent in these patients, being associated with an increase in mortality and morbidity and worse social outcomes. This study aims to understand the relationship between Schizophrenia and substance use disorders (SUD).
Material and methods: A retrospective study was designed, including patients diagnosed with schizophrenia admitted to the Psychiatric Ward between January 2017 and June 2019.
Results: 205 patients were included, 49 women (23.9%) and 156 men (76.1%). Of these, 29.1% consumed psychoactive substances at the first hospitalization, mainly cannabis (24.1%), with higher prevalence in men.
The average age at the first admission was significantly lower for substance users than for non-users. The presence of consumption in the first hospitalization, the number of hospitalizations and treatment adherence were asso- ciated with the maintenance of consumption after the first hospitalization. The presence of consumption at the first hospitalization is a significant predictor of its maintenance. Patients who do not adhere to treatment were more likely to maintain consumption. The number of future hospitalizations was associated with early age at the first hospitalization, non-compliance to treatment and maintenance of consumption after the first hospitalization.
Conclusions: We verify that the consumption of psychoactive substances is associated with the early age at the first hospitalization, whit the reduced compliance to treatment and the increased number of hospitalizations.
Comorbid substance use disorders should be treated as early as possible to minimize the long-term effects of substance use on patients with schizophrenia in Dual Diagnosis programs.
Psychiatry 2021; 18, 3: 182–189
Key words: schizophrenia, dual diagnosis, substance use disorder, cannabis
Introduction
the substance use disorder (SUD) is very common in people with psychiatric disorders, although this asso- ciation is difficult to establish. Psychoactive substance consumption can lead to the development of psychiatric symptoms or trigger an underlying chronic mental illness but, on the other hand, mental illness can increase sub- stance use as a way of relieving psychiatric symptoms.
This led to the concern of the scientific community to
understand and study the relationship between SUD and mental illness, coining the term “dual pathology”
to designate patients who have at least one addition in comorbidity with a psychiatric disorder.
Although this topic is a well-studied and presented in the literature, there are only scarce references to research in the area.
According to the World Drug Report 2020 [1], it is es- timated that in 2018 around 269 million people of the world population had used drugs at least once in the previous year, corresponding to 5.4% between 15–64 years of age. Cannabis use remains the most problematic (192 million people in 2018, 3.9% of the total population aged 15–64) and opioids the most harmful. In 2018, 35.6 million people experienced substance use disorders.
Approximately 47% of patients with Schizophrenia consume psychoactive substances, compared with a prevalence of 16% in the general population, and meet the criteria for a dual diagnosis [2]. In addition to to- bacco and alcohol, the consumption of illicit substances, particularly cannabis, is quite prevalent in people with Schizophrenia [3]. There is a growing number of diagno- sis of psychosis associated with SUD, with a prevalence of consumption in the first psychotic episode between 30–70% [4]. The SUD in people with Schizophrenia is associated with increased mortality and morbidity, earlier onset of the disease and worst prognosis with the highest number of hospitalizations, abandonment of therapy, more legal problems due to increased violence, higher suicide rates and higher health costs [5]. Also, the qual- ity of life of dual patients is impaired particularly in the mental domain when compared to patients with severe mental illness alone or substance use dependence [6].
The full aims of this study are: 1) to analyze a cohort of patients diagnosed with schizophrenia (F20) with comor- bidity with SUD (F10-F19), with emphasis on illicit drugs;
2) to clarify the psychoactive substances consumption pattern at the first hospitalization, according to age and gender; 3) to understand the factors that may influence the number of hospitalizations and the maintenance of consumption in this population.
Material and methods
This study included patients followed up at the Integra- ted Psychiatric Responsibility Center at Coimbra Hospital and University Center (CHUC). The data collection period was between January 2017 and June 2019, including hospitalization analysis and follow-up during this period.
The data were collected through hospital information systems (SClínico and Oracle), using a standardized form for data collection. Data collection interviews were not conducted with patients or family members.
The patients included were diagnosed with Schizop- hrenia (F20.0), with or without substance use disorder (F10-F19) according to the 10th Revision of the Interna- tional Classification of Diseases (ICD-10), had at least one admission into a Psychiatric ward and were followed-up in Psychiatry at CHUC. Patients followed-up in other hospital centers were excluded from the study even though they were admitted to CHUC. Patients who had is first hospitalization in another hospital center, where also excluded from this study. In total, 205 patients were eligible for the study.
After creating the database, statistical analysis was per- formed based on the SPSS 25.0 software (IBM SPSS Sta- tistics 25). A descriptive analysis of the sample variables was performed and tests of independence and measures
of association were made based on the t-Student test. In order to analyze possible association factors for variables, linear and logistic regression methods were performed.
This work was written according to the STROBE guideli- nes and approved by the CHUC Ethics Committee.
Results
Sample description
The sample consisted of 205 patients, corresponding to 49 women (23.9%) and 156 men (76.1%).
The mean age of male was 45 years with a standard deviation of 14 and, the mean age of female was 50 years with a standard deviation of 13. The average age of the sample was 46.38 years, with a significant difference between men and women (t = 0.028, p < 0.05) (Table 1).
The average age at the first hospital admission was approximately 32 years, with a minimum age of 15 years and a maximum age of 72 years (Table 2). The age difference between male and female at first ho- spital admission was statistically significant (t = 0.002, p < 0.05), with men having a first hospitalization at earlier ages (M = 30.3, F = 36.4).
The average duration of the first hospital stay was 28.8 days (Table 2), with no significant difference be- tween men and women (M = 27.26, F = 33.91, t = 0.108, p > 0.05). With regard to the number of hospitalizations, there was an average of 5 hospitalizations (Table 2), with also no significant difference between women and men (M = 5.35, F = 3.81, t = 0.066, p > 0.05).
Regarding the number of missing appointments, the average was approximately 3 appointments (Table 2), with no significant differences between men and women (M = 2.92, F = 2.10, t = 0.214, p > 0.05).
Lack of adherence to treatment was define by early discontinuation of medication at the first follow-up appointment after the first hospitalization. The majo- rity of patients did not adhere to treatment (n = 121, 60.8%). About 94 patients (45.9%) were hospitalized on a compulsive basis or maintained follow-up in a com- pulsory outpatient setting and 11.2% (n = 23) had legal problems (Table 3).
Consumption of psychoactive substances and dual diagnosis
Of the 205 patients in the sample with the main diag- nosis of Schizophrenia, 29.1% (n = 58) had SUD when they were first admitted to the psychiatric service, that is they were actively using psychoactive substances around their first hospitalization.
Cannabis was the most consumed drug (n = 48, 24.1%) (Table 4). Of the 58 patients who had SUD on the first
hospitalization, 57 were men (38.0%) and only 1 was a woman (2.0%).
Maintenance of consumption is defined by the per- sistence of consumption at least in one additional hospitalization.
After the first hospitalization in Psychiatry, 40 patients had SUD (20.3%). Of these, 34 (17.3%) maintained can- nabis use, cocaine use increased to 4.6% (n = 9), heroin use decreased to 6.2% (n = 12), ecstasy use (MMDA or methylenedioxyamphetamine) remained unchanged (n = 1, 0.5%), the use of LSD (lysergic acid diethylamide) decreased to 1% (n = 2) and the use of amphetamines decreased to 0 (Table 4).
When we analyzed the age at the first hospitalization according to the presence of consumption of psycho- active substances, we noticed that the age of consumers (C) and non-consumers (NC) was significantly different (t = 0.000, p < 0.05), with the mean age of those who consumed the lowest (C = 26.71 versus NC = 34.22).
Conversely, there was no further significant difference between these two groups either in terms of the num- ber of subsequent hospitalizations (NC = 4.51, C = 5.90, t = 0.079, p > 0.05), in the duration of the first hospi- Table 1. Sociodemographic characterization of the sample
Age
n % Mean SD Med. Min. Max.
Gender Male 156 76.1 45 14 44 20 81
Female 49 23.9 50 13 48 24 76
Civil status Single 164 82.8
Married 16 8.1
Divorced 11 5.6
De facto union 2 1.0
Widower 5 2.5
Housing area Rural 112 56.0
Urban 88 44.0
Support type None 26 14.0
Family 120 64.5
Institution 40 21.5
Education Primary school 1 3.4
Middle school 3 10.3
Secundary school 12 41.4
University 13 44.8
Table 2. Sample characterization in relation to hospitalizations and missing appointments
n Mean SD Min. Max.
Number of hospitalizations 202 4.99 5.029 1 34
Duration of the first hospitalization 151 28.75 21.250 0 180
Age at the first hospitalization 185 31.76 11.608 15 72
Missing appointments 182 2.74 3.661 0 17
Table 3. Characterization of the sample in relation to adherence to treatment, the need for compulso- ry hospitalization regime or outpatient compulsory care and the presence of legal problems
No Yes
n % n %
Adherence to treatment
121 60.8 78 39.2
Compulsory regime 111 54.1 94 45.9
Legal problems 182 88.8 23 11.2
talization (NC = 29.90, C = 25.43, t = 0.240, p > 0.05) or in the number of missing appointments (NC = 2.57, C
= 3.12, t = 0.378, p > 0.05).
The main diagnosis of Schizophrenia (F20.0) is present in all patients studied. Of the comorbid diagnoses, the most common, present in 7.8% of the sample, was Mental and behavioural disorders due to use of cannabinoids (F12.1) (Table 5).
Prediction of number of hospitalizations In order to infer prediction models that explain what fac- tors may influence the number of hospitalizations presen- ted, a linear regression was performed and the variable number of hospitalizations was analyzed as a dependent variable. The independent variables considered were gender, age, age of the first hospitalization, duration of the first hospitalization, SUD at the first hospitalization, maintenance of consumption, adherence to treatment, compulsory regime and legal problems. For this purpose,
a stepwise forward multiple regression was performed.
The dependent variable number of hospitalizations, positive asymmetric, approaches normality with a lo- garithmic transformation, so we opted for the variable thus transformed.
The final model obtained allowed us to conclude that 49% of the variance in the distribution of the number of hospitalizations was explained by predictors such as age, age at the first hospitalization, maintenance of consumption after the first hospitalization and treatment adherence (adjusted R2 = 0.494).
Age at the first hospitalization varies inversely with the number of hospitalizations, so the lower the patient’s age at the first hospitalization the greater the number of hospitalizations that the patient will have.
Likewise, the lower the adherence to treatment, the greater the number of hospitalizations that the patient will present. The persistence of SUD is similarly related to the number of hospitalizations, thus the maintenance of Table 5. Discrimination and quantification of primary and secondary diagnoses
Primary diagnosis ICD-10 Code n %
Schizophrenia F20.0 205 100
Secundary diagnosis ICD-10 Code n %
Multiple drug use and use of other psychoactive substances F19 13 6.3
Use of alcohol: harmful use F10.1 12 5.9
Use of alcohol: dependence syndrome F10.2 9 4.4
Use of opioids: dependence syndrome F11.2 2 1.0
Use of cannabinoids: harmful use F12.1 16 7.8
Use of cannabinoids: dependence syndrome F12.2 12 5.9
Use of cannabinoids: unspecified mental and behavioural disorder F12.9 3 1.5
Use of sedatives or hypnotics: acute intoxication F13.10 1 0.5
ICD: International Statistical Classification of Diseases, 10th revision
Table 4. Typology of drug use in the first hospitalization and maintenance after the first hospitalization
First hospitalization After the first hospitalization
No Yes No Yes
n % n % n % n %
Cannabis 151 75.9 48 24.1 162 82.7 34 17.3
Cocaine 193 97.0 6 3.0 187 95.4 9 4.6
Opioids 183 92.0 16 8.0 182 93.8 12 6.2
LSD 196 98.5 3 1.5 194 99.0 2 1.0
Ecstasy 198 99.5 1 0.5 195 99.5 1 0.5
Amphetamines 197 99.5 1 0.5 198 100 0 0
LSD: lysergic acid diethylamide
consumption after the first hospitalization contributed to the increase in the number of future hospitalizations.
Prediction of the maintenance of consumption after the first hospitalization
Through the logistic regression model, it was possible to analyze the variable maintenance of consumption as a dependent variable. The independent variables consi- dered in this model were gender, age, age at the first hospitalization, duration of the first hospitalization, SUD at the first hospitalization, number of hospitalizations, missed appointments, adherence to treatment and compulsory regime. For this purpose, a stepwise forward logistic regression was performed.
Based on the Hosmer Lemeshow test value = 0.877 (p > 0.05), we conclude that the predicted values estima- ted by the model are close to the observed values, that is, the model is adequate. This model has a sensitivity of 90.3% (3 false negatives) and a specificity of 92.3%
(7 false positives).
The model correctly classifies 91.8% of the sample cases in which the model was estimated, with an increase of 17.2% comparing to the null model. According to the Wald test, only the variables number of hospitalizations (12,297, p = 0.000), SUD at the first hospitalization (21,348, p = 0.000) and treatment adherence (3,380, p = 0.006) were significant in the model.
Discussion
We found a considerable percentage of patients with Schizophrenia and a comorbid SUD, with 29.1% of consumers at the first psychiatric hospitalization.
The main gender differences found were the earlier age of first hospitalization in men with a difference of 6 years compared to women, and the higher prevalence of SUD in men in the first psychiatric hospitalization.
The most illicit substance consumed was cannabis (Table 5).
The age of patients at the first hospitalization seems to be affected by substance consumption, with consu- mers having a first hospitalization at an earlier age than non-consumers with a difference of 7 years. After the first psychiatric hospitalization, 20.3% of the patients continued to consume, and cannabis remained the most consumed drug (Table 5).
The number of hospitalizations was influenced by age, age at the first hospitalization, maintenance of con- sumption after the first hospitalization and treatment adherence. The younger the patient’s age at the first hospitalization, the greater the number of future hospita- lizations. The percentage of non-adherence to treatment found is quite significant (Table 3) and also influences the likelihood that the patient will have more hospitaliza-
tions compared to those who follow the treatment. The maintenance of substances consumption after the first hospitalization contributed significantly to the greater number of hospitalizations compared to non-consumers.
The presence of consumption in the first hospitalization, the number of hospitalizations and treatment adherence were associated with the maintenance of consumption after the first hospitalization. The presence of consump- tion at the first hospitalization is a significant predictor of its maintenance. Likewise, patients who do not adhere to treatment were more likely to maintain consumption.
In 2019, Dependencies and Addictive Behaviours In- tervention Service (SICAD) reported a prevalence of SUD in the last 12 months of about 5% [7].
Previous studies show that consumption of illicit sub- stances, especially cannabis, is common in patients with schizophrenia [8]. A recent systematic review found a higher prevalence of cannabis use in FEP (36%) when compared to patients with chronic schizophrenia (22%) [3]. On the other hand, the use of cannabis at the onset of the disease is associated with continued consumption for several years despite the possible adverse conse- quences [9], as demonstrated by our study in which 17.3% of patients maintained cannabis use after the first hospitalization.
A retrospective study conducted at the Psychiatric Service of Leiria included a pool of 471 patients with psychotic symptoms admitted to the psychiatric ward between 2011 and 2013. In 38.3% of the patients, a causal rela- tionship between cannabis consumption and psychotic symptomatology was assumed, and the diagnosis in FEP was substance-induced psychosis [10]. This study also reported a higher prevalence of SUD in males (87%) and a lower mean age in the FEP in consumers in relation to non-consumers [10], which is in line with the results found in our study.
In a retrospective study made in Denmark between 1994 and 2016, data on psychiatric diagnoses collected from a nationwide Danish registers found that an increase in dual diagnosis with schizophrenia and cannabis use disorder parallel to the development of cannabis-induced psychosis [11].
The consumption of stimulant substances, such as cocaine or amphetamines, was more prevalent in the studied patients than in the general Portuguese popu- lation (Cocaine 0.2%; Amphetamines 0.1% in the last 12 months) [7]. Even so, the consumption of stimulants is lower comparing to previous studies that reported prevalence of stimulant consumption of 7.3% in patients with schizophrenia [3]. This finding is easily understand- able given the lower consumption of these substances in our country when compared to other regions.
The induction of psychotic symptoms by the consump- tion of stimulant substances is widely described in the literature [12], with increasing evidence that the consumption of these substances can induce behav- ioral, neurochemical and molecular alterations typical of schizophrenia.
The association between schizophrenia and substance consumption has been studied and, although it is not yet fully understood, some hypotheses have been presented for this association. There are several studies linking the cannabis consume with the earlier onset of psychosis and the risk of developing schizophrenia [8, 13–17].
On the one hand, substance consumption can act as an environmental stressor, precipitating psychotic symptoms. This hypothesis would also explain the earlier onset of symptoms in these patients found in this study and widely reproduced in the literature [18]. Other au- thors suggest that patients with schizophrenia consume psychoactive substances to reduce the symptoms of the disease itself or the side effects of the medication [19].
However, this hypothesis does not explain the cases where SUD precedes the onset of symptoms. Substance consumption may also serve as an attempt to counter the dopaminergic dysfunction of the reward system [20, 21].
Finally, the shared genetic risk or the presence of pre- existing brain abnormalities can predispose individuals to develop both schizophrenia and SUD [22–24].
The earlier onset of psychotic symptoms in men is widely described in the literature [3, 25]. In our study there was also a higher prevalence of SUD in males. As SUD is associated with an earlier onset of symptoms, it can contribute significantly to the gender differences found.
In accordance with previous studies [26], we found high rates of lack adherence to treatment (60.8%) in the studied population. The substance abuse/depen- dence is a factor known to be commonly involved in non-adherence to treatment in patients with schizo- phrenia [27]. Since the benefit of antipsychotic therapy in reducing relapse in patients with schizophrenia is unquestionable, lower adherence to therapy may explain the greater number of hospitalizations in patients with SUD. On the other hand, patients with treatment adher- ence who also maintained substances consumption had higher readmission rates than patients with treatment adherence without SUD [28]. This highlights that high number of hospitalizations in patients with SUD is not only related to the poor adherence to treatment but also to the effects of the psychoactive substances themselves.
The comorbidity with substance use disorders in patients with schizophrenia contributes to a worse prognosis, promoting an earlier onset of the disease, less adherence to treatment and a higher number of relapses and hospital-
izations [5]. Thus, comorbid substance use disorders should be treated as early as possible to minimize the long-term effects of substance use on patients with schizophrenia. In these patients, the application of programs for substance use disorders developed for patients without comorbidity with psychotic disorders will be less effective. To overcome these difficulties, Dual Diagnosis programs should be implemented, in which the treatment of schizophrenia is integrated with the treatment of substance use, allowing patients to acquire strategies to manage both psychiatric disorders, as well as promoting therapeutic compliance, functionality and integration in the community [29, 30].
As so, non-pharmacological strategies such as the estab- lishment of a therapeutic alliance with long term clinical commitment, psychoeducation to the patient and his family and cognitive behavioral therapy aimed abstinence, must be implemented. Accessible mental health services for all patients, with the capacity to promote the rapid reinte- gration of those who miss appointments also contributes to a better outcome. In addition, simplified therapeutic regimens, considering the introduction of long-acting in- jectable antipsychotic, contribute to treatment compliance [31, 32]. Since the side effects of antipsychotics are some- times responsible for non-adherence to the treatment, the clinician must monitor its appearance and not devalue their burden on the patient.
Our study has a few strengths and limitations. One strength is the fact that we present follow-up data up to two and a half years for a large sample of patients with dual diagnosis of schizophrenia and substance use disorder.
One of the limitations of the study is the lack of data regarding the first episode psychosis (FEP), making it impossible to infer from the consulted records the percentage of patients in which the first hospitalization corresponded to the FEP. The lack of data regarding the period between the onset of the disease and the psychia- tric intervention also represents a limitation of the study.
Another limitation is the lack of data about the reasons that led to non-adherence to therapy, namely the pre- sence of side effects of antipsychotics or the existence of memory loss/cognitive impairment.
The risk of alcohol use disorders were found to be more than twice in psychotic disorders comparing to general population [33, 34]. Another limitation of the study is the inconsistency of the data found regarding the con- sumption of alcohol by the patients, with few clinical reports describing the consumption pattern, leading to a small percentage of patients in this study diagnosed with a comorbid alcohol disorder (Table 5).
Tobacco is one of the psychoactive substances most consumed by patients with Schizophrenia [35, 36].
However, the reports and clinical records consulted did not address this data, so we could not include it in our study. This aspect can be possibly explained by the devaluation by the clinicians of the consumption of tobacco among the patients with Schizophrenia.
So, a limitation of this study is the lack of a systematic method of substance use that was applied routinely to all patients at the hospital.
Conclusions
This study showed frequent substance use at the first hospitalization for schizophrenia, especially in men.
Additionally, there was also a high prevalence of con- sumption in subsequent hospitalizations, which was related to consumption in the first hospitalization and non-adherence to the proposed treatment. Substance use in these patients is associated with earlier hospi- talizations, less adherence to treatment and a higher number of hospitalizations during the study period. Since these are factors of poor prognosis for the evolution of schizophrenia, intervention in substance use should be promoted and integrated with the treatment of schizop- hrenia through the implementation of Dual Diagnosis programs. Future studies should consider our findings and our study limitations in order to improve knowledge in this matter and adequate treatment programs to these specific population.
References
1. United Nations Office on Drugs and Crime. World Drug Report.
United Nations publication 2020.
2. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990; 264(19):
2511–2518, indexed in Pubmed: 2232018.
3. Hunt GE, Large MM, Cleary M, et al. Prevalence of comorbid sub- stance use in schizophrenia spectrum disorders in community and clinical settings, 1990-2017: Systematic review and meta-analysis.
Drug Alcohol Depend. 2018; 191: 234–258, doi: 10.1016/j.dru- galcdep.2018.07.011, indexed in Pubmed: 30153606.
4. Abdel-Baki A, Ouellet-Plamondon C, Salvat É, et al. Symptomatic and functional outcomes of substance use disorder persistence 2 years after admission to a first-episode psychosis program. Psychiatry Res. 2017; 247: 113–119, doi: 10.1016/j.psychres.2016.11.007, indexed in Pubmed: 27888680.
5. Green AI, Khokhar JY. Addiction and schizophrenia: A translatio- nal perspective. Schizophr Res. 2018; 194: 1–3, doi: 10.1016/j.
schres.2017.10.008, indexed in Pubmed: 29046253.
6. Benaiges I, Prat G, Adan A. Health-related quality of life in patients with dual diagnosis: clinical correlates. Health Qual Life Outcomes.
2012; 10: 106, doi: 10.1186/1477-7525-10-106, indexed in Pubmed: 22950596.
7. Serviço de Intervenção nos Comportamentos Aditivos e nas Dependências: Direção de Serviços de Monitorização e Informação / Divisão de Estatística e Investigação. Relatório Anual 2018. A situação do país em matéria de drogas e toxicodependências. SICAD 2019.
8. Toxicodependências. Serviço de Intervenção nos Comportamentos Aditivos e nas Dependências 2019.
9. Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizop- hrenia and substance use disorder: A unifying hypothesis. Schizophr Res. 2018; 194: 78–85, doi: 10.1016/j.schres.2017.04.016, indexed in Pubmed: 28416205.
10. Myles H, Myles N, Large M. Cannabis use in first episode psychosis:
Meta-analysis of prevalence, and the time course of initiation and continued use. Aust N Z J Psychiatry. 2016; 50(3): 208–219, doi:
10.1177/0004867415599846, indexed in Pubmed: 26286531.
11. Associação Portuguesa de Patologia Dual. Doença psiquiátrica e adicção. Chiado editora, Lisboa 2016.
12. Hjorthøj C, Larsen MO, Starzer MS, et al. Annual incidence of can- nabis-induced psychosis, other substance-induced psychoses and dually diagnosed schizophrenia and cannabis use disorder in Den- mark from 1994 to 2016. Psychol Med. 2021; 51(4): 617–622, doi:
10.1017/S0033291719003532, indexed in Pubmed: 31839011.
13. Areal LB, Herlinger AL, Pelição FS, et al. Crack cocaine inhalation induces schizophrenia-like symptoms and molecular alterations in mice prefrontal cortex. J Psychiatr Res. 2017; 91: 57–63, doi: 10.1016/j.jpsychires.2017.03.005, indexed in Pubmed:
28314129.
14. Vaucher J, Keating BJ, Lasserre AM, et al. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry.
2018; 23(5): 1287–1292, doi: 10.1038/mp.2016.252, indexed in Pubmed: 28115737.
15. Marconi A, Di Forti M, Lewis CM, et al. Meta-analysis of the as- sociation between the level of cannabis use and risk of psychosis.
Schizophr Bull. 2016; 42(5): 1262–1269, doi: 10.1093/schbul/
sbw003, indexed in Pubmed: 26884547.
16. Belbasis L, Köhler CA, Stefanis N, et al. Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses. Acta Psychiatr Scand. 2018; 137(2):
88–97, doi: 10.1111/acps.12847, indexed in Pubmed: 29288491.
17. Foti DJ, Kotov R, Guey LT, et al. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization.
Am J Psychiatry. 2010; 167(8): 987–993, doi: 10.1176/appi.
ajp.2010.09020189, indexed in Pubmed: 20478874.
18. Ortiz-Medina MB, Perea M, Torales J, et al. Cannabis consumption and psychosis or schizophrenia development. Int J Soc Psychiatry.
2018; 64(7): 690–704, doi: 10.1177/0020764018801690, inde- xed in Pubmed: 30442059.
19. Barnes TRE, Mutsatsa SH, Hutton SB, et al. Comorbid substance use and age at onset of schizophrenia. Br J Psychiatry. 2006; 188:
237–242, doi: 10.1192/bjp.bp.104.007237, indexed in Pubmed:
16507965.
20. Lowe DJE, Sasiadek JD, Coles AS, et al. Cannabis and mental illness: a review. Eur Arch Psychiatry Clin Neurosci. 2019; 269(1):
107–120, doi: 10.1007/s00406-018-0970-7, indexed in Pubmed:
30564886.
21. Volkow ND, Michaelides M, Baler R. The neuroscience of drug reward and addiction. Physiol Rev. 2019; 99(4): 2115–2140, doi:
10.1152/physrev.00014.2018, indexed in Pubmed: 31507244.
22. Wise RA, Koob GF. The development and maintenance of drug addiction. Neuropsychopharmacology. 2014; 39(2): 254–262, doi:
10.1038/npp.2013.261, indexed in Pubmed: 24121188.
23. Thoma P, Daum I. Comorbid substance use disorder in schizop- hrenia: a selective overview of neurobiological and cognitive un- derpinnings. Psychiatry Clin Neurosci. 2013; 67(6): 367–383, doi:
10.1111/pcn.12072, indexed in Pubmed: 23890122.
24. Petersen SM, Toftdahl NG, Nordentoft M, et al. Schizophrenia is associated with increased risk of subsequent substance abuse diag- nosis: A nation-wide population-based register study. Addiction.
2019; 114(12): 2217–2226, doi: 10.1111/add.14746, indexed in Pubmed: 31301685.
25. Adan A, Arredondo AY, Capella MD, et al. Neurobiological un- derpinnings and modulating factors in schizophrenia spectrum disorders with a comorbid substance use disorder: A systematic review. Neurosci Biobehav Rev. 2017; 75: 361–377, doi: 10.1016/j.
neubiorev.2017.01.038, indexed in Pubmed: 28188887.
26. Li R, Ma X, Wang G, et al. Why sex differences in schizophrenia?
J Transl Neurosci (Beijing). 2016; 1(1): 37–42, indexed in Pubmed:
29152382.
27. Phan SV. Medication adherence in patients with schizop- hrenia. Int J Psychiatry Med. 2016; 51(2): 211–219, doi:
10.1177/0091217416636601, indexed in Pubmed: 27079779.
28. García S, Martínez-Cengotitabengoa M, López-Zurbano S, et al.
Adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: A systematic review. J Clin Psychopharmacol.
2016; 36(4): 355–371, doi: 10.1097/JCP.0000000000000523, indexed in Pubmed: 27307187.
29. Hunt GE, Bergen J, Bashir M. Medication compliance and comorbid substance abuse in schizophrenia: impact on community survival 4 years after a relapse. Schizophr Res. 2002; 54(3): 253–264, doi: 10.1016/s0920-9964(01)00261-4, indexed in Pubmed:
11950550.
30. Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv. 2001;
52(4): 469–476, doi: 10.1176/appi.ps.52.4.469, indexed in Pubmed: 11274491.
31. Marquez-Arrico JE, Río-Martínez L, Navarro JF, et al. Coping strate- gies in male patients under treatment for substance use disorders and/or severe mental illness: influence in clinical course at one-year follow-up. J Clin Med. 2019; 8(11), doi: 10.3390/jcm8111972, indexed in Pubmed: 31739487.
32. Correll CU, Citrome L, Haddad PM, et al. The use of long-acting inje- ctable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016; 77(suppl 3): 1–24, doi: 10.4088/JCP.15032su1, indexed in Pubmed: 27732772.
33. Kane JM, Correll CU. Optimizing treatment choices to improve adhe- rence and outcomes in schizophrenia. J Clin Psychiatry. 2019; 80(5), doi: 10.4088/JCP.IN18031AH1C, indexed in Pubmed: 31536686.
34. Archibald L, Brunette MF, Wallin DJ, et al. Alcohol use disorder and schizophrenia or schizoaffective disorder. Alcohol Res. 2019; 40(1), doi: 10.35946/arcr.v40.1.06, indexed in Pubmed: 31886105.
35. Hartz SM, Pato CN, Medeiros H, et al. Genomic Psychiatry Cohort Con- sortium. Comorbidity of severe psychotic disorders with measures of substance use. JAMA Psychiatry. 2014; 71(3): 248–254, doi: 10.1001/
jamapsychiatry.2013.3726, indexed in Pubmed: 24382686.
36. Sagud M, Mihaljevic Peles A, Pivac N. Smoking in schizophrenia:
recent findings about an old problem. Curr Opin Psychiatry. 2019;
32(5): 402–408, doi: 10.1097/YCO.0000000000000529, indexed in Pubmed: 31135490.
37. Caponnetto P, Polosa R, Caponnetto P, et al. Tobacco smoking, related harm and motivation to quit smoking in people with schi- zophrenia spectrum disorders. Health Psychol Res. 2020; 8(1): 9042, doi: 10.4081/hpr.2020.9042, indexed in Pubmed: 32510003.
