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Volume 15, Issue 3, Year 2015

ROMANIAN JOURNAL OF
PSYCHOPHARMACOLOGY

Editura Medical Universitar Craiova


2015

CONTENTS

Clinical Predictors of the Antidepressant Treatment Response in Patients with Major Depressive
Episode Treated with Agomelatine in a Multicenter, Prospective, Observational Study............................... 117
Traian Purnichi, Valentin Petre Matei, Felicia Militaru, Ileana Marinescu,
George Laurentiu Paraschiv, Ioana Pavel
Therapeutical Approaches in the Schizo-Obsessive Paradigm ...................................................................... 124
Brindusa Ecaterina Focseneanu, Iuliana Dobrescu, Gabriela Marian, Veronica Rusanu
Metabolic Syndrome and Its Relationship with Cognitive Deficits in Schizophrenia .................................... 135
Andreea Codruta Botis, Ioana Miclutia
The Aggressive Conduct in Persons with Personality Disorders and Forensic Consequences ..................... 147
Alexandra Bolos, Vasile Chirita, Roxana Chirita
Predisposing and Precipitating Factors in Refractory Depression ............................................................... 156
Ghenadie Carausu, Alina Crasmari, Eugenia Sinita
Relationship Between Cannabis and Psychosis: Challenges and Controversies ........................................... 163
El Hadi Zerdazi, Maria Ladea, Andrei Szke, Ion Udristoiu, Marion Leboyer,
Franck Schrhoff, Aziz Ferchiou

Romanian Journal of Psychopharmacology

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Romanian Journal of Psychopharmacology (2015) 15, 117-123

CLINICAL PREDICTORS OF THE ANTIDEPRESSANT TREATMENT


RESPONSE IN PATIENTS WITH MAJOR DEPRESSIVE EPISODE
TREATED WITH AGOMELATINE IN A MULTICENTER,
PROSPECTIVE, OBSERVATIONAL STUDY
Traian Purnichi1, Valentin Petre Matei2, Felicia Militaru3*, Ileana Marinescu3,
George Laurentiu Paraschiv3, Ioana Pavel1
1
Al. Obregia Psychiatric Hospital Bucharest, Romania
2
University of Medicine Carol Davila Bucharest, Romania
3
University of Medicine and Pharmacy of Craiova, Romania

Abstract
Introduction: Major Depressive Disorder (MDD) is a heterogeneous,
complex and debilitating disorder that increases the burden of patients,
families and society. The response to the antidepressant treatment varies
largely, but literature reported several correlations of age, patients
characteristics and duration of depression with the response to
antidepressant treatment.
The objective of this observational study was to evaluate the daily
functionality in MDD patients under AD treatment, who were prospectively
followed. The secondary objectives included the improvement of MDE
severity and symptoms and the adherence to the AD treatment.
Method: 1194 patients were included with a first MDE or a recurrent MDE
according to the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV-TR), age between 18 and 75 years, treated with agomelatine before
the inclusion in the study. The prospective observation of the patients lasted
for 10 weeks and included 4 visits: V0- baseline, V1- after 2 weeks, V2- after
6 weeks and V3 - after 10 weeks. For the evaluation of the MDE we used the
CGI scale and the Quick Inventory of Depressive Symptomatology scale
(QIDS-16). The statistical analysis was done using Kynos Modalisa software
with a confidence level of 95%.
Results: Age, recurrent MDD and duration of depression were and diagnosis
delay were found to predict the negative course of the disorder.
Conclusions: We noticed a concordance of the results of this study with the
data from the literature regarding the results: age, MDD duration, number of
MDE and time from diagnostics to treatment are the main clinical predictors
of the antidepressant treatment response.
Keywords: depression, antidepressants, predictors.

*Correspondence: Felicia Militaru, Clinica de Psihiatrie Craiova, Aleea Potelu 24, 200317 Craiova, Romania.
E-mail: feliciobanu@yahoo.com
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Introduction
Major Depressive Disorder (MDD) is a heterogeneous, complex and debilitating disorder with a
tremendous burden on patients, their family and society [1]. The literature data are showing that
almost 52% of patients with MDE have persistent and important symptomatology compared to 18%
of patients with mild MDE that experience major difficulties in daily social interactions [2].
Even if the available antidepressants (AD) help patients to obtain a good response or remission of
symptoms, there is a period of several weeks until their entire pharmacological action is perceived
by patients and clinicians.
There are still significant controversies regarding the moment when the symptomatic amelioration
became significant on the evolution of Major Depressive Episode (MDE) treated with AD. Even
though several methodological limitations exist (like the focusing on the clinical response rather
than upon symptomatology remission), the results collected from randomized clinical trials (RCT),
meta-analyses and observational studies show that: (A). in general AD are associated with early
amelioration of the symptoms which can be observed in the first 2 weeks since antidepressant
treatment initiation (defined as a reduction 20% in depression severity measured by standardized
rating scales); (B) several antidepressants like agomelatine are associated with early amelioration of
both central symptomatology (depressed mood and anhedonia) and specific symptoms like sleepwake disturbances; (C) early amelioration is a predictor of symptomatology remission and early
response. Subsequently, the lack of amelioration could be seen as a predictor of non-response [3].
Therefore it is of tremendous importance to identify predictors of response to antidepressant.
According to analytical studies on factors and groups there has been shown that depressive mood
(negative emotions), anhedonia and psychomotor symptoms are the elements that define major
depressive disorders the best [4]. Diverse studies showed that anhedonia can precede the onset of a
depressive episode, it can influence its severity, can be a predictor of a bad outcome 12 months later
and it is a residual symptom frequently present. The inclusion of patients in subtypes according to
the type of symptoms and phenomenological approach could constitute a further step of the future
psychopharmacology in order to prescribe the best antidepressant according to specific symptoms.
There are articles on this subject in the literature but until now the results are not yet conclusive [5].
Despite significant advances in neuroscience, treatment development didnt keep the pace. The
main reason is because we dont have yet applicable clinical neuroimaging or other biomarkers. For
the time being there are none widely accepted bio- markers available to assist diagnostics, treatment
choice or predictors of response for individual patients. Therefore, we still need to rely on
demographical and clinical data in order to try to predict antidepressant response in depressed
patients. However, owing to the overwhelming biological and clinical heterogeneity of depression,
it is implausible that any single clinical or biological marker can guide treatment se- lection. Rather,
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in Patients with Major Depressive Episode Treated with

multiple biological measures together with clinical and demographical ones may be needed to refine
our understanding of the pathology and guidance of treatment.

Methods
Participants
The study population was constituted of in and outpatients from 59 representative centers in
Romania. The investigators were psychiatrists working in the public health system (hospital or
specialized ambulatory) or in private practice. The observational study took place between 1st of
February 2012 and 8th of June 2012.
In the study were included 1194 patients with a first MDE or a recurrent MDE according to the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) [6], over 18 years old but
under 75 years, whose doctors recommended agomelatine before the inclusion in the study and who
accepted in common agreement with their clinician to be monitored during study. In the final
analysis we also included patients with bipolar disorder (2.68%, n=32) and patients without
specification of MDE (10%, n=125) due to the fact that this was a naturalistic study and these
diagnostics were modified after baseline.
Out of 1194 MDE patients included in the study, more than half (645 patients) were with recurrent
MDE. The exclusion criteria referred to the patients that: (A) went to the doctor in emergency
regime, (B) use of psychoactive substances, (C) have an age under 18 years or above 75 years and
(D) presented serious comorbidities and/or severe pathology which could affect their participation
in the study (hepatic impairment, limited cooperation, legal limited capacity, another severe nonpsychiatric disorder, cancer, medication abuse, severe cardiovascular disease or renal failure).
The main objective of this observational study was the evaluation of daily functionality in MDD
patients under AD treatment, who were prospectively followed. The secondary objectives included
MDE severity improvement and MDD symptomatology evolution in these patients and the
adherence to the AD treatment.
The prospective observation of the patients lasted for 10 weeks and included 4 visits: V0- baseline,
V1- 2 weeks since inclusion, V2 and V3 at 6 respectively 10 weeks since inclusion. At the initial
visit (baseline), depressive mood, anhedonia and focusing difficulties/decision making were the
most prominent symptoms as measured with QDIS-C16 scale.
Instruments
In order to evaluate the MDE it was used standards instruments: CGI scale (Clinical Global
Impressions Scale). The CGI scale is an instrument through which the clinician evaluates 3 different
global parameters (7):
A. The severity of the disease: global evaluation of actual severity of patient's symptoms (CGI-S);
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Traian Purnichi et al.

B. The global improvement: general comparison between patient's actual state and the initial
(baseline) state (CGI-I);
C. Efficacy index: general comparison between patient's initial state and a rapport between the
actual therapeutic benefit and severity of adverse reactions (CGI-E).
For severity evaluation of MDE it was used the Quick Inventory of Depressive Symptomatology
scale (QIDS-C16 - Rush et al., 2003). The QIDS16 scale includes all the symptomatology domains,
which was developed on the base of DSM-IV criteria for diagnosis of major depressive episode
[8,9]: 4 items for evaluation of sleep disturbances; 2 items for evaluation of psychomotor
disturbances (agitation or slowing of the psychomotor function); 4 for appetite/ weight evaluation
(increasing/decreasing of appetite and weight gain/loss) and only one item for evaluating the other 6
domains (depressed mood, low interest, decreased level of energy, feelings of inutility/ guilt,
concentration/decision making difficulties, suicidal ideation). Each item is evaluated on a scale
from 0 to 3. For the domains that require the evaluation of least 2 items, the highest score is
considered. For example if at the beginning of sleep the value of insomnia is 0, the value of
insomnia the middle of the night sleep is 1, for morning insomnia is 3 and 0 for hypersomnia, then
the sleep disturbances domain gains a total score of 4 points. The total score varies between 0 and
27. The reference interval in the evaluation of symptoms severity is the 7 days period prior to
evaluation. QIDS is sensitive to the change of the clinical state status associated with medical
treatment, psychotherapy or somatic treatment, being a very good instrument in both research and
clinical practice.
The degree of adherence to the treatment throughout study development was evaluated by the
number of pills declared by the patient as taken from one visit to another. The study was
prospective, observational and longitudinal; all the participants signed an inform consent before
being included into the study.
The statistical analysis was done by CEGEDIM Company using Kynos Modalisa software with a
confidence level of 95%, a maximum sampling error for all patients of 2.81% and p-value. The
level of analyses was: all CRFs, splits on patient categories, e.g. gender, age categories. The
indicators were: absolute and relative frequencies for categorical variable; central tendency
indicators for quantitative variables; confidence levels provided in annex. Significance tests that
were made: Fishers F test testing for significant differences among pre-defined groups; z-test for
means, t-test for matched samples testing for significant differences between visits; Chi2 test
testing for association among pre-defined groups.

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Clinical Predictors of the Antidepressant Treatment Response


in Patients with Major Depressive Episode Treated with

Results
Demographic characteristics
Women represented 68% of the population (n=1190) with a mean age of 48 years. A higher
representation had the patients included in the 55 to 60 years age group (18%), followed by patients
in the 50 to 55 age group (17%) (n=1186). The lowest representation in the group was for the
patients under 25 years (3%). No gender differences were seen regarding the type of episode and
the duration of anterior affliction in patients with a current major depressive episode.
Clinical predictors of the antidepressant treatment response
The statistics revealed that while all the patients presented a significant improvement of the
symptomatology, some categories have registered more progress, as follows:
Age: The elderly patients (age between 65 and 75) have a slower improvement than other age
categories, for all the visits (p=0.002 at V1, p=0.001 at V2 and V3);
Major depressive episode (new/recurrent): it has been noted significant differences between the
patients with a new major depressive episode and recurrent in all that concerns the total scores
(ANOVA), but the items scores (Chi2). The patients with recurrent MDD had a slowly recovery.
Disorder duration (<3 months/ 3-6 months/ 6-12 months/>12 months): it has been noted
differences at the last visit, where the patients with recently diagnosed with MDE (<3
months) had a better recovery. Also the patients with a MDE diagnosed more than 12 months
ago have a slower recovery than other categories.
Also, patients with recent diagnosed and treated MDE (<3 months) had better significant
CGI-S scores at the end of the 10 weeks period in contrast with the patients who had MDE
symptoms for more than 1 year (F=4.027; p=0.001).
At the same time, by comparing the patients with recurrent MDE with the patients with a new
diagnosed MDE, the last category has a significant higher rate of improvement (total scores
and individual scores). The differences have been observed from the first visit.

Discussions
We noticed a concordance of the results of this study with the data from the literature regarding
the results.
The group of patients enrolled in this study had a moderate symptomatology and this could be
explained by the fact that patients who were addressing to the emergency services were excluded.
Another explanation could be the presence of the residual symptoms in patients with recurrent
depression and their treatment was changed because of the loss of therapeutic response (the main
reason of the changing anterior treatment in this study).
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For this group of patients, the symptomatology domains at the initial moments and who had a
considerable improvement starting with the second week of treatment have been represented by the
depressed mood, loss of concentration and making decisions and anhedonia. Of the three domains,
after ten weeks of treatment anhedonia presented a better improvement. Considering that the
medication for the study was represented exclusively by agomelatine, it is possible that this
substance plays an important role which could confirm the results of the recent studies [4, 10].
In this study, the patients recently diagnosed (<3 months) and treated have presented a significant
improvement after ten weeks of treatment compared with the patients diagnosed with depression
more than one year before. Also, the patients with more than 65 years old diagnosed with
depression more than one year before had a slow improvement during all the visits. These two
observations sustain the importance of recognizing depression and the initiation of the treatment
from the beginning, which allow a good improvement of the functionality.
No side effects related to the AD treatment were recorded according to the clinicians judgment.
Considering that the medication was based almost exclusively on agomelatine, the results of the
study can be considered representative for this substance.

Conclusions
This study results revealed as main clinical predictor for the response to the antidepressant
treatment the following criteria:
Age: The elderly patients have a slower improvement than other age categories, for all the
visits.
Clinical evolution: the patients with recurrent MDE had a slower recovery.
Duration chronic depression and longer depressive episodes are associated with slower and
poorer response.

Disclosures
The authors declare that received in the past grants from Servier Pharma and other speaker fees.
In addition all the authors received in the past speakers fees and/or sponsorship from Servier
Pharma and others companies for scientific research or communication. Dr. Traian Purnichi
works also as a marketing specialist for Servier Pharma and Dr. George Paraschiv is an employee
of Servier Pharma.
Acknowledgements
All the authors had an equal contribution and have similar rights. All the authors approved the final
version of this article.
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Clinical Predictors of the Antidepressant Treatment Response


in Patients with Major Depressive Episode Treated with

The authors will like to thank:


Cegedim Company that did the statistical analysis using a Kynos Modalisa software.
Medinteractiv Plus for helping on the study draft.
Servier Pharma for offering the grant that made this study possible.
Financial support
This study was founded by a grant from Servier Pharma.

References
1. C de Bodinat, B Guardiala-Lemaitre, E Mocaer, P Renard, C Munoz, MJ Millan:
Agomelatine, the first melatonergic antidepressant: discovery, characterization and
development, Nature Reviews, Vol 9, August 2010, 628-642.
2. R.W. Lam, H. Mok: Depression, Oxford University Press, New York, 2008.
3. R.W. Lam: Onset, time course and trajectories of improvement with antidepressants,
European Neuropsychopharmacology (2012) 22, S492-S498.
4. M di Giannantonio, G Martinotti: Anhedonia and major depression: the role of agomelatine,
European Neuropsychopharmacology (2012) 22, S505-S510.
5. G. Hasler, WC Drevets, HK Manji, DS Charney, Discovering endophenotypes for major
depression, Neuropsycjopharmacology (2004), 29, 1765-1781.
6. APA, Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatry
Association Press, Washington DC. Text revision, 2000.
7. Forkmann T et al, The clinical global impression scale and the influence of patient or staff
perspective on outcome, BMC Psychiatry, 2011, 11:83.
8. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan
PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-item Quick Inventory
of Depressive Symptomatology (QIDS) Clinician Rating (QIDS-C) and Self-Report (QIDSSR): A psychometric evaluation in patients with chronic major depression. Biological
Psychiatry, 54:573-583, 2003.
9. www.ids-qids.org, pagina de internet pentru instrumentele IDS/QIDS, accesat n 16 aprilie 2013.
10. G Martinotti, G Sepede, F Gambi, G Di Iorio, D de Berardis, M di Nicola, M Onofrj, L Janiri,
M di Giannantonio: Agomelatine versus Venlafaxine XR in the treatment of anhedonia in
major depressive disorder: a pilot study, J Clin Psychopharmacology, 2012, 32 (4): 487-491.

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Romanian Journal of Psychopharmacology (2015) 15, 124-134

THERAPEUTICAL APPROACHES
IN THE SCHIZO-OBSESSIVE PARADIGM
Brindusa Ecaterina Focseneanu1*, Iuliana Dobrescu2, Gabriela Marian1, Veronica Rusanu3
1
Titu Maiorescu University, Faculty of Medicine, Bucharest, Romania
2
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
3
Clinical Emergency Hospital, Bucharest, Romania

Abstract
The association of obsessive-compulsive symptoms in schizophrenia has
created, during the last decade, in the scientific world, a remarkable interest
to solve the underlying pathophysiological mechanisms and the clinical and
evolutionary exploration of the psychopathologic image. The increased
prevalence of these symptoms in schizophrenia, the impact, mainly negative,
on the evolutionary flow which the psychotic disorder tends to follow in its
chronic stage and the therapeutic challenges feed the interest for this
psychiatric entity. Although there is a general consensus that this category of
patients comprises is a difficult-to-treat subtype, research addressing
treatment interventions is still in the initial stage. The psychotic vulnerability
of these patients at the action of the antiserotonergic drugs, the antipsychotic
filter which must be applied in the therapeutic choice, taking into account the
pro-obsessive activity of certain psychopharmacological agents and the
susceptibility to side effects such as extrapyramidal symptoms or akatisia
make difficult the therapeutic undertaking and call for the constant reshuffle
of the clinical and therapeutic approach.
Keywords: schizophrenia, obsessive-compulsive symptoms, pharmacotherapy.

Introduction
After the amendment of the DSM diagnostics criteria excluding comorbidity within schizophrenia in
1987 [1], a remarkable increase of the co-morbidity of schizophrenia with disorders of the obsessivecompulsive spectrum (OC) was noticed. The obsessive-compulsive symptoms and the obsessivecompulsive disorder (OCD) associated with schizophrenia have clinical implications characterized by
a larger malfunction, a lower quality of life, the increase of the number of suicide attempts and a more
reduced social network [2]. However, the prevalence rates of the obsessive-compulsive
symptomatology in schizophrenia showed striking variations. Obsessions and compulsions that are
not severe enough to meet the criteria for OCD were reported with a frequency of up to 64% [3] in
schizophrenia, while TOC recorded rates between 0 and 59 % in various studies [4]. These rates attest
*Correspondence: Brindusa Ecaterina Focseneanu, Titu Maiorescu University, Faculty of Medicine, 67A Gheorghe
Petrascu Str., District 3, 031593 Bucharest, Romania. Tel./Fax: +40727742402, E-mail: brindusa.ionescu@gmail.com.
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Therapeutical Approaches in the Schizo-Obsessive Paradigm

that obsessive-compulsive symptoms are most commonly associated with schizophrenia than in the
general population, where the recorded average prevalence is of 1.6% [5]. And even if it is known
the fact that schizophrenia is often associated with various comorbidities, the difference between the
prevalence rates of symptoms of obsessive-compulsive disorder in schizophrenia is higher than the
combination with other anxiety or depression disorders [6].

Clinical course of OC symptoms associated with the image of schizophrenia


Between the various sub-groups of patients with schizophrenia and OC pathology, are noticed both
the different moment of occurrence of OC symptoms, as well as differences regarding the
longitudinal evolution of the severity of these symptoms.
First signs of the OC symptoms in schizophrenia
The onset of the OC symptoms was described in various stages during the psychotic disorder (1)
before the psychosis, as an independent syndrome, diagnosed as OCD; (2) before the psychotic
manifestation, as part of at risk mental state (ARMS); (3) parallel to the first manifestation of
psychosis; (4) in the course of chronic schizophrenia; (5) de novo onset or worsening after initiation
of the antipsychotic treatment.
Epidemiological data vary within limits which are quite broad due to the differences of criteria used for
the diagnostic of ARMS or in the psychometric defining and assessment of the OC and OCD
symptoms. A sub-group of patients shows OC symptoms ever since the period of high risk for
psychosis, the average prevalence being of 12,1% (9.4-14.8%) for OC symptoms [7], and of 5.2% (4.1
to 6.3%) for OCD [7]. Among the patients who are at the first psychotic episode, the rates increase
slightly, being recorded an average prevalence of 17.1% for OC symptoms (14.0-20.2%) and of 7.3%
(5.3-9.3%) for OCD [7,8]. The presence of OC symptoms in the ARMS period seems to have a clinical
impact on other clinical variables, although the data reported are not homogeneous. The results show a
higher negative impact on the psycho-social functioning [8] and the association of several depressive
symptoms [8]. The effects of OC symptoms on the conversion rates of ARMS to psychosis are
contradictory [9]. The interventional study PREVENT (Secondary Prevention of Schizophrenia: A
Randomized Controlled Trial) [10] allowed the multidimensional assessment of a band of 233 patients
who were in the ARMS period, of these 26 meeting the criteria for OCD or having a history of OC
symptoms, finding that these patients were more severely affected at the level of the general psychopathology and the psycho-social functioning, but not at the level of the defective symptoms or the
cognitive abilities. There is a sub-category of patients developing OC symptoms de novo, during
schizophrenia, the prevalence being considerably higher compared to the previous stages (12% for OCD
and 25% for OC symptoms) [6] and another sub-category, underestimated, developing OC symptoms
after the initiation of the treatment with atypical antipsychotics.
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The impact of obsessive-compulsive symptoms on the evolution of schizophrenia


Longitudinal studies, very few, which investigated the quantitative modifications of the severity of
OC symptoms during the evolutionary development of schizophrenia, have described the
predominance of a fluctuating course of the severity of OC symptoms, although the OC symptoms
may persist and even worse, in time, especially in patients with OCD preceding the psychotic
episode. These have a higher risk for a persistent evolution, with worsening, in time, of the OC
symptoms, independently of the evolution of schizophrenia [11]. A Dutch study performed for 5
years shows that 70% of the patients with schizophrenia and OC pathology show a fluctuating
evolution of the OC symptoms, some patients experiencing remission, while others showed a more
or less cyclic evolution. The rest of them registered the persistence of the severity of OC symptoms
[12]. Schirmbeck et al. led to a longitudinal study in Germany on schizophrenic patients treated
with antipsychotic in mono-therapy and found the persistence of the severity of OC symptoms after
12 months of treatment in the group treated with clozapine and olanzapine, unlike the much lower
rates registered in the group treated with amisulpride and aripiprazole [13, 14]. Besides the diversity
of the clinical image of this co-morbidity, the various evolutionary routes of the OC symptoms
along the evolution of schizophrenia add a plus to this heterogeneity and suggest the involvement of
certain varied etiologic factors.
There are an increasing number of studies exploring the impact of obsessions and compulsions on
the functioning of patients with schizophrenia and on the evolutionary course of schizophrenia.
These parameters seem to be more severe, also accumulating a higher frequency of neuropsychiatric
issues in schizophrenia. However, there are contradictory studies regarding the severity of positive
or negative symptoms in these patients with schizophrenia and OCD. From most of the studies [it
shows the fact that schizophrenia with OC/OCD symptoms was associated with: poorer global,
social, economic and vocational functioning; earlier onset of schizophrenia; a larger use of the
medical services/hospitalizations; a more severe clinical image; social isolation; resistance to
treatment; a more severe long-term prognostic; higher depression scores increasing the risk of
suicide; a poorer cognitive functioning and predominant damage of certain specific cognitive areas;
more neuroanatomic abnormalities starting with the onset; higher levels of positive symptoms and
more emotional discomfort on versus less positive symptoms and less plat effect on the first episode
of schizophrenia; predominance of negative symptoms of schizophrenia versus less negative
symptoms; the total score per positive symptoms PANSS is correlated with the total one on the YBOCS scale; paranoid symptoms and symptoms of first degree of schizophrenia; the treatment with
antipsychotics may induce or exaggerate the obsessive-compulsive symptoms and may even induce
OCD; the symptoms may become resistant to treatment [12-17]. Therefore, it is important the
precision of the diagnostics of schizophrenia and OCD because current treatments differ for each of
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them and the first-line medication for one of them may exaggerate the symptoms of the other:
antipsychotics may exaggerate the symptoms of OC and the SSRIs may exaggerate psychosis [15].
Obsessive-compulsive pathology induced by the atypical antipsychotic treatment
The first reports of the OC symptoms as side effects induced by the treatment with atypical
antipsychotic treatment were published by Baker et al. [18] and De Haan et al. [19]. Ever since,
more studies have shown a clear association between atypical antipsychotics and OC symptoms
[20], especially in the case of clozapine [16], the explanation proposed being the pro-obsessive
effect of the atypical antipsychotics.
During the treatment with first-generation antipsychotics, there were rarely reports of adverse effects
such as obsessive-compulsive symptoms. Some authors proposed a pharmaco-dynamic mechanism
attributing the OC symptoms to the anti-dopamine and anti-serotonin properties, especially on the
5-HT1C, 5-HT2A, and 5-HT2C receptors [21], of the second-generation antipsychotics, in contrast
with the low affinity of the first-generation ones for serotonin receptors [22].
Studies have shown that the obsessive-compulsive symptoms may be induced or exaggerated by the
high doses of pro-obsessive antipsychotics, increasing the antagonist affinity on the 5-HT2A
receptors [23] while the extended duration of the treatment leads to the increase of the regulation of
the expression of these receptors [20]. If certain first-generation antipsychotics, such as haloperidol,
showed even antiobsessional effects, when administered as adjutants in the treatment of resistant
OCD [24], second-generation antipsychotics sparked a lot of controversies

by their

pharmacological particularities, different from their traditional homologous.


There were also researched the different effects of the 2 generations of antipsychotics on the
glutamatergic neurotransmission [25]. Poyurovski et al. estimated that up to 70% of the patients
with schizophrenia treated with pro-obsessive antipsychotic agents develop secondary OC
symptoms [15], while Lykouras et al., revising the data published, reported the presence of OC
symptoms de novo in 77% of the patients treated with clozapine [26], and other authors reported
estimations between 74% and 89% [20,23]. Unlike the pro-obsessive effect of clozapine,
aripiprazole, partially dopamine and serotonin agonist, was associated with an antiobsessive effect
in the patients with schizophrenia and associated OC pathology [27], nearly similar to amisulpride,
antagonist of dopamine receptors D3/D2 [28].

Schirmbeck et al. [20] finds OC co-morbid

symptoms with schizophrenia in more than 70% of the patients treated with clozapine or olanzapine
and only in less than 10% in those treated with amisulpride or aripiprazole.
Recent researches have proven that the severity of OC symptoms positively correlates with the
duration of the treatment with clozapine or olanzapine [20,29] and with the dose and serum level of
clozapine [20]. Other studies have shown, however, contradictory results, the increase [30] or the
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decrease of the dose of clozapine [26] or the initiation of the treatment with olanzapine [31]
showing the improvement of the OC symptoms. A possible explanation is that of the difficulty of
the differentiation between the OC symptoms and the catatonic symptoms or delusional ideas. The
patients who present obsessive ruminations or stereotypical thoughts during the acute phase of the
disease or repetitive ritualistic behaviours obviously related to the psychotic condition may benefit
from treatment with clozapine. There were also reported positive effects of the antipsychotics in
OCD resistant to serotonin antidepressants, even for olanzapine [24].
Doyle et al. [32] trying to differentiate the type of OC symptoms induced by clozapine by a
phenotypic approach, noticed that in these patients it predominates the dubitation, unlike the
patients with primary OCD, where prevail the compulsions related to washing.
Poyurovsky [33] resumes clinical features of OC symptoms induced by antipsychotics, as it
follows: men are more susceptible than women; schizophrenics with pre-existing OC symptoms are
at high risk; OC symptoms are like the ones met in OCD and differ from the content of delusional
ideas and hallucinations; however, predominate the compulsions vs. obsessions; OC symptoms
induced by olanzapine, risperidone or quetiapine tend to appear during the first weeks of treatment,
while those induced by clozapine have either an early onset (during the first 12 weeks of treatment)
or a late onset (after 12 weeks of treatment); olanzapine induces OC symptoms in varied doses (525mg/day), while risperidone in higher doses (over 3mg/day), as well as quetiapine (4501100m/day; clozapine induces OC symptoms either in small doses (150-250mg/day, in case of early
onset, either in high doses (350-900mg/day), in case of late onset.

Therapeutic approaches of schizo-obsessive pathology


The facilitation of the development of some efficient therapeutic interventions depends on the
recognition of biological mechanisms and the effects of the variables given by the environmental
factors on the emergence and evolution of OC symptoms.
Pharmacotherapy
The pharmacological approach of the pure OC symptoms imply the administration as therapeutic
first-line of SSRI or the clomipramine, but it was found that a part of the patients (40-60%) [34]
become refractory to this approach and the replacement with an antipsychotic has often proved to be
inefficient, sometimes leading to the development or intensification of psychotic symptoms.
Augmentation strategies of the antidepressant medication (SSRI or clomipramine) with the
antipsychotic one (risperidone, haloperidol, quetiapine-equivocal results, olanzapine or aripiprazole)
proved to be efficient according to several case studies and some clinical trials [24, 35, 36].
Based on the current knowledge, were suggested combined and augmentation pharmacological
strategies to improve the OC symptoms co-morbid to schizophrenia [16, 33]. To cut the possible
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Therapeutical Approaches in the Schizo-Obsessive Paradigm

pro-obsessive effects of second generation antipsychotics, which are mainly antiserotonergic it was
proposed the addition of atypical antipsychotics mainly dopamine, such as amisulpride and
aripiprazole. In the augmentation strategies, it was assessed the treatment with serotonin
antidepressants, e.g., with tricyclic antidepressants, such as clomipramine or with SSRI such as
fluvoxamine [37]. The results of these studies were inconsistent, certain studies reporting the
significant decrease of the OC symptoms, while others could not prove this effect. The notable
secondary anticholinergic effects and the pharmacokinetic interactions must be taken into
consideration upon combining the drugs. However, preliminary results suggest promising outcomes
in case of augmentation with mood stabilizers, such as valproic acid [38] or lamotrigine [39].
Schizo-obsessive patients seem to be more vulnerable to developing motor adverse effects under
treatment with antipsychotic agents, SSRI or combinations thereof, supporting the hypothesis of a
frontal-basal nodes connection underlying the schizo-obsessive pathology. The SSRI medication
attenuates the dopamine transmission and induces, indirectly, extrapyramidal effects and akathisia
in 10% of the non-schizophrenics patients [33], and to the addition of antipsychotics with the strong
antagonist action at the level of the D2 receptors, the risk to develop the extrapyramidal effects
increases more. In addition, there is the problem of the differential diagnostic of these motor
disturbances; akathisia can be confused with motor stereotypes in schizophrenia or with ritual
behaviors in OCD. Parkinsonian bradykinesia must be differentiated from the schizophrenic
ambivalence or by the pathological doubtful of OCD. It is, therefore, needed a clinical assessment
in dynamics to determine the temporal feature of the association between the administration of the
pharmacological agent and the emergence of the extrapyramidal symptoms, as well as their
modification in time. If it is shown the iatrogenic feature, it is recommended the reduction of the
dose of antipsychotic/SSRI and shall be added anticholinergic agents and/or beta blockers for
cropping and extrapyramidal symptoms and of akathisia. It is even more difficult to address these
secondary motor phenomena in the presence of catatonic symptoms quite frequently reported in
these patients (stereotypes, mannerisms, ECOP triad, grimaces, catalepsy) and sketched, even
before the introduction of antipsychotics, the image of mannerism catatonia, notion describing the
sub-type of schizophrenia with catatonia and OC symptoms [33].
Cognitive-behavioral therapy
The patients who recently reported modifications of the OC symptoms might be investigated using
the Experience Sampling Method, capturing the individual's reactivity to environmental factors and
the evolution of symptoms detailed daily in real-life situations. Collecting these information helps
identifying the evolutionary moment of occurrence of the changes at the level of the symptom and
its relation with vital contextual triggers of the variability. The results of the studies conducted by
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this method might provide important information for customized interventions, including adjusted
modules of cognitive-behavioral therapy. However, so far, there are very limited data regarding the
efficiency and safety of the cognitive-behavioral therapy for the patients with co-morbid
schizophrenia with OC symptoms. A recent analysis of the case reports and of a series of published
cases, it summarized data collected from 30 co-morbid patients, who were treated by cognitivebehavioral therapy, including elements of exposure or only the exposure and the prevention of the
response [16]. The results have shown favorable outcomes with a significant decrease of OCD
severity in 24 patients. Within the series of cases analyzed by Tundo et al. [40] more than 50% of
the people receiving cognitive-behavioral therapy were classified as more or a lot more improved.
Despite the adverse clinical results in 10% of the patients and a total dropout rate of 20%, the
preliminary results suggest the significant and marked decrease of the severity of OC symptoms in
80% of the participants [16].
In conclusion, the available evidence is limited to small number of cases. Therefore, more
controlled clinical trials are needed to manage more efficiently the issue of the co-morbidity of
schizophrenia-OCD.
Resistance to treatment
Due to the limited perspective on the biological mechanisms of schizophrenia and of OCD, treatment
means are limited to a few strategies. Therefore, a large part of the patients do not respond enough to
treatment, even if the doctors follow the guidelines for the multi-modal approach of schizophrenia or
OCD. Faced with the patients resisting the treatment, the poly-pharmacological strategies are often
used in schizophrenia, as well as in OCD. Therefore, there is no wonder that this co-morbidity
requires a broader pallet of approaches in research and in identifying the therapeutic options.
The potentially iatrogenic action of clozapine and olanzapine, especially at high doses and/or long
term should be studied in patients where the onset of OC symptoms is after the onset of psychosis,
alongside reconsidering the risk/benefit of maintaining clozapine as treatment for refractory
psychosis. There is also the option of linking to aripiprazole to the clozapine regimen, which has the
advantage of having an antiobsessional action, while being able to reduce the dose of clozapine.
Another option in the resistance to treatment or when the severity of symptoms endangers the physical
and mental integrity of the individual is the electroconvulsive therapy, several case reports underlying
its benefit also in the schizo-obsessive patients, the stigma associated with this procedure and the
patient's agreement must be considered before its execution [33]. Besides the electroconvulsive therapy,
a future direction of therapeutic research should also consider the deep brain stimulation.
Overall, all the empirical evidence support a newly created diagnosed entity named schizoobsessive disorder representing a nosologic construct for a more severe evolution and prognostic
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Therapeutical Approaches in the Schizo-Obsessive Paradigm

that the OCD or pure schizophrenia. Despite all these findings, there are still certain questions to
clear, related to the distinctive features of the schizo-obsessive patients. The most important
consists in differentiated answer to psycho-pharmacological interventions, a variable which was not
considered in any prospective comparative study.

Conclusion
Patients with schizophrenia should be evaluated for OC symptomatology before starting or
switching to an atypical antipsychotic. They also should be monitored prospectively for the
emergence of de novo OC symptoms. So far, therapeutic researches on schizo-obsessive patients
have been oriented towards the treatment of co-morbid obsessive symptoms, being noticed a
significant decrease by the use of antidepressants, antipsychotics, mood stabilizers and,
exceptionally, by the use of the electroconvulsive therapy and the deep brain stimulation. In this
decision tree, the use of antidepressants as medication of first choice should be reconsidered, when
the assessment of the psychotic symptoms might be exacerbated by their use.
Taking into account the pro-obsessive activity of certain psychopharmacological agents, the
susceptibility to extrapyramidal symptoms or akathisia which can create confusion about the nature
of symptoms, there is a general consensus that this group of patients represents a difficult-to-treat
subtype. The latest researches try to offer an insight into biological mechanism of the pathogenesis
of the comorbid condition and to estimate the effects of relevant environmental variables on the
development and course of OC symptoms in schizophrenia in order to facilitate the development of
innovative and effective treatment interventions.
Disclosure. All authors declare no conflicts of interest.

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Romanian Journal of Psychopharmacology (2015) 15, 135-146

METABOLIC SYNDROME AND ITS RELATIONSHIP


WITH COGNITIVE DEFICITS IN SCHIZOPHRENIA
Andreea Codruta Botis*, Ioana Miclutia
University of Medicne and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romania

Abstract
Metabolic syndrome in patients with schizophrenia remains a challenge,
not only because it increases the relative cardiovascular risk but also
because it interferes with many domains of functioning, including
neurocognitive functions.
More than atypical antipsychotics, which are now the most common
treatment in schizophrenia, risk factors for metabolic syndrome have not been
yet well identified and pathophysiological links between them are not yet well
clarified. This way, if there is a metabolic threshold for antipsychotics and its
significance, if there is a correlation between negative symptoms and
metabolic syndrome, if treating metabolic syndrome could improve cognition
in schizophrenia are current research topics. This paper aims to review the
data currently available regarding these topics.
Keywords: schizophrenia, metabolic syndrome, cognition.

Introduction
With a prevalence of approximately 1%, schizophrenia is among the first ten causes of chronic
disability worldwide, causing burden in multiple aspects of social, family and professional life [1].
Life expectancy for schizophrenia patients is 15-20 years shorter, and the mortality rate is 2.5-3
times higher compared to the general population. Suicide and accidents represent around 40% of the
total of death causes for patients with schizophrenia; somatic pathology accounts for the rest of 60%
[2]. In the past few years, the concern for investigating somatic pathology increased regarding
patients with schizophrenia, especially for cardiovascular pathology [3]. While assessing the link
between symptoms and mortality causes for patients with psychotic pathologies, Hayes et al have
depicted the fact that mortality has not been associated in a statistically significant way with
positive symptomatology (hallucinations, delusions or aggressive behavior), but it has a statistically
significant correlation with associated somatic pathology [4].
The metabolic syndrome connects a series of anthropometric and biological parameters which are
predictive factors for cardiovascular pathology and mortality: dyslipidemia, hyperglycemia, central

*Correspondence: Andreea Codruta Botis, email: mihailescu.andreea@umfcluj.ro.


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Andreea Codruta Botis et al.

obesity and hypertension. The metabolic syndrome increases the relative cardiovascular risk by 1.22 times [5].
In a recent meta-analysis, Mitchell et al showed that one in three schizophrenia patients fulfill the
metabolic syndrome criteria, one in two patients is overweight, one in five patients has significant
hyperglycemia scores for the prediabetes diagnosis and at least two out of five patients have
dyslipidemia [6]. Patients with schizophrenia present a cardiovascular risk two times higher
compared to the general population and the patients in their first schizophrenic episode [7].
The exact data on the prevalence of the metabolic syndrome of schizophrenia patients is unknown,
and it varies between 11-69% for patients undergoing treatment and between 4 and 26% for
untreated patients [8].
In the clinical study Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) carried
out on 1231 patients, McEnvoy at al identified a prevalence of the metabolic syndrome of 40.9%
according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP
III) and one of 42.7% according to International Diabetes Federation IDF definitions [9].
The CLAMORS multicentric study carried out on 1452 patients in Spain, Bobes at al. reported a
24.6% prevalence of the metabolic syndrome [10].
There are minor differences concerning the prevalence of the metabolic syndrome in schizophrenic
patients depending on the country where the study has been conducted: 32.5% in USA, 34.5% in
Finland, 30.1% in Turkey, 30.2% in Spain [6].
As for the prevalence of the individual factors that define the metabolic syndrome, in a recent metaanalysis of 126 studies including 25,692 patients with the disorders average extent of 10.4 years,
Mitchell at al determined a percentage of 49.4% of overweight patients, 19.5% of hyperglycemic
patients, 39.3% with hypertriglyceridemia, 42.6% with low scores of HDL-Col, 38.7% with high
blood pressure, 54.2% smokers and 10.9% with diabetes [6].
Most studies from the scientific literature are cross-sectional and estimate the prevalence of the
metabolic syndrome for patients who already undergo antipsychotic treatment. The number of
longitudinal prospective studies, valuable when it comes to information that explains the
mechanisms of occurrence and the evolution of the metabolic syndrome, is limited in the literature.
A naturalistic study carried out by Mackin et al in which patients were examined on a 4 years
period, emphasized that patients treated with antipsychotics have a high cardiovascular risk, but,
except central obesity, the cardio-metabolic profile did not change in a substantial way during
observation period [11].

Risk factors for metabolic syndrome for patients with schizophrenia


The occurrence of the metabolic syndrome is based on a mechanism that is still unclear. The
etiology is multifactorial.
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Cognitive Deficits in Schizophrenia

De Hert identified three complementary factors which partially overlap: lifestyle, and antipsychotic
medication and mental disorder related issues [12].
Patients with schizophrenia have a sedentary lifestyle with low physical activity, an inadequate diet
rich in saturated fat and poor in fibers and fruits, therefore being susceptible to obesity [13].
Obesity, as a component of the metabolic syndrome, has a high prevalence in schizophrenia patients
compared to the general population [14].
Schizophrenic patients smoke, consume alcohol, coffee, salt and saturated fats more frequently. The
smoking prevalence is three times higher for schizophrenia patients compared to the general
population, and the number of smoked cigarettes for schizophrenic patients is higher than the
general population [15]. In a Finnish study carried out on subjects with psychotic pathology, the
smoking habit along with diabetes mellitus was described as the most important predictors for
mortality after 8 years. [16].
Roick et al has documented the association of an inadequate diet with a poor economic status of
schizophrenia patients caused by the disability of these patients when it comes to paid labor [17].
Other studies showed that patients with schizophrenia have an even more inadequate diet than the
most financially disadvantaged social classes. This situation could be correlated with negative
symptomatology. Characteristics of negative symptomatology such as apathy, decrease in
motivation and lack of interest for hygiene and physical appearance determine these patients
preference for an unhealthy and easy to obtain diet [12].
The mechanisms involved in the development of metabolic changes due to antipsychotics still
represent a debate subject. Also, the metabolic disorders associated with atypical antipsychotics
represent an extra challenge in regards of schizophrenia patients treatment. These affect all ages,
but there is data showing that younger patients are more vulnerable when it comes to developing
metabolic syndrome as a consequence of antipsychotic treatment [18].
The risk of developing metabolic syndrome differs depending on age, sex, ethnicity - observed as
influencing factors of the metabolic effects occurrence risk. There are also individual particularities
and currently unclear mechanisms related to antipsychotics metabolic effects.
The prevalence of obesity for schizophrenic patients treated with antipsychotics is between 40-60%
compared to 30% for the general population. Atypical antipsychotics determine more frequently
and more visibly a significant weight gain (defined as more than 7% of the initial weight) compared
to typical antipsychotics [19].
The weight gain associated with the atypical antipsychotic treatment was identified by Pogge et al
as their only side effect which predict non-adherence to treatment [20].
The mechanisms involved in the weight gain caused by antipsychotics are complex and currently
not clear enough. The differentiated receptoral profile of antipsychotics is to be blamed. The
muscarinic, histaminic and serotoninergic antagonism determines a more emphasized weight gain.
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Also, these drugs could induce weight gain by interfering with the dopaminergic reward system
which determines appetite gain [21]. Other factors discussed in the literature that may be possibly
involved in the weight gain mechanism under neuroleptic treatment are: the folate and
hyperhomocysteinemia modified metabolism, and also genetic markers that predispose certain
patients to gain weight [22].
Atypical antipsychotics also modify other metabolic syndrome parameters: dyslipidemia and
glucose blood level elevation.
The prevalence of diabetes mellitus for patients with schizophrenia is of 16-25%, 2-4 times higher
than in the general population. The adherence to hypoglycemic treatment for schizophrenia patients
is approximately 50% making the prognosis of this comorbidity worse [23]. Most cases of
antipsychotic-related diabetes mellitus appear in the first six months of neuroleptic treatment, and
these glycemia changes are often reversible once the treatment with the responsible antipsychotic is
interrupted, suggesting the direct action of the antipsychotic over the pancreatic function [24]. The
mechanisms involved in the occurrence of diabetes induced by antipsychotics are unclear. While the
weight gain caused by antipsychotics is frequently associated with hyperglycemia and diabetes
mellitus, this disease also occurs independently from the weight gain while under antipsychotic
treatment. The anticholinergic effect of antipsychotics over the insulin secretion inhibition, the
peripheral resistance to insulin caused by hyperprolactinemia induced by antipsychotics, the
resistance to leptin are all hypotheses discussed in the literature as possible mechanisms involved in
the antipsychotic-related diabetes mellitus.
It is not known whether there are specific intimate mechanisms through which antipsychotics cause
dyslipidemia or if it is linked to those responsible for gaining weight and developing diabetes mellitus.
Despite the evidence of antipsychotics inducing metabolic changes, there is no solid proof of a link
between antipsychotics and mortality rate increase of schizophrenic patients. In a recent metaanalysis, Khan et al concluded that the use of antipsychotics did not correlate with increased
mortality for psychiatric patients, although the high mortality for these patients cannot be
questioned [25]. A prospective cohort study carried out for eleven years showed that long term
mortality in patients treated with antipsychotic is reduced compared to untreated schizophrenic
subjects [26]. A possible explanation would be a better somatic monitoring of these patients. The
debates in the scientific literature about the results of this study are still ongoing. Prospective
studies are necessary, with direct measurement and adjustment of all known risk factors involved in
schizophrenia-related premature mortality taking into consideration the metabolic traits modified by
them and, subsequently, the high cardiovascular risk [27].
The concept called "the antipsychotics metabolic threshold refers to the fact that these drugs could
induce metabolic disorders, especially weight gain with the purpose of activating certain restoring
mechanisms necessary for the improvement of clinical symptomatology and suggest the existence of a
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possible link between antipsychotics side effects, especially weight gain and improvements in
clinical symptomatology. Metabolic changes could represent a measurement for symptomatology
improvement. According to this concept, in a recent review of the literature, 14 out of the 15
analyzed studies described a positive correlation between the favorable evolution of the
symptomatology, especially general psychopathology, and weight gain. The authors concluded that
Olanzapine and Clozapine showed this relationship consistently [28]. Leptin, a hormone produced by
adipose cells could be the mediating factor in this relationship. A recent meta-analysis which retrieved
twenty eight studies about the leptin serum level changes induced by antipsychotics concluded that
the most significant leptin increases were observed with antipsychotics inducing the most weight gain.
There was also observed an association between leptin elevation and BMI changes [29]. On the other
hand, there are studies which suggest that increase in leptin serum level correlates with clinical
improvement in schizophrenia [30]. Further studies need to consider certain confusion factors in order
to verify the authenticity of the metabolic threshold concept, to find the pathophysiological links
and its importance in predicting the clinical response to antipsychotic treatment.
In a recent study carried out on 1120 patients with schizophrenia treated with various atypical
antipsychotics, out of which 52.2% were assessed with one or more negative symptoms, the metabolic
syndrome prevalence was significantly higher in the group of patients with negative symptomatology
(43.9%) compared to the group of patients without negative symptoms (34.9%) [31]. Also, the
metabolic syndrome had a statistically significant correlation with negative symptomatology, age and
somatic comorbidities. Other results suggest that negative symptomatology is predominant on the
symptomatology assessment using the Positive and Negative Symptoms Scale (PANSS) [32]. In a
study carried out on 372 schizophrenic patients treated with antipsychotic for more than two years,
Chen et al showed that negative symptomatology was negatively correlated with the body mass index
and triglycerides serum level, and positively correlated with HDL-Col, authors suggesting that
patients with negative symptomatology could have a different lipid profile compared to those without
significant negative symptoms [33].
Further studies are needed in order to find out whether there are significant correlations between
clinical symptomatology and the metabolic syndrome and the intimate mechanisms they are based on.
When it comes to schizophrenic patients, there have been described changes in the functioning of
the hypothalamic-pituitary-adrenal axis with secondary hypercholesterolemia and its phenotypic
expression in central obesity. The role of schizophrenia, as a disorder, is discussed as an
independent risk factor for developing metabolic syndrome. Therefore, the studies carried out on
schizophrenic patients who are not treated with neuroleptic medication present the best accuracy.
Such studies are limited in number, and only a few investigate the whole spectrum of changes that
characterize the metabolic syndrome. In a review of the literature provided by Reddy et al with the
purpose of assessing the link between schizophrenia and the metabolic syndrome, unrelated to
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antipsychotic medication, an average metabolic syndrome prevalence of 10,8% was determined for
untreated patients in their first schizophrenic episode and subsequently diagnosed with this disorder
The authors of this literature review suggest that the frequency of the metabolic syndrome of
untreated patients, diagnosed with schizophrenia and those having their first episode is not
statistically different, regarding the frequency of the metabolic syndrome in subjects without mental
disorders, comparable to age and sex [24]. However, schizophrenia itself can be suspected to be a
risk factor in developing certain components of the metabolic syndrome. The untreated patients who
are in their first psychotic episode present high scores of glucose serum levels, low glucose
tolerance, high scores of insulin serum levels and insulin resistance, high scores of blood cortisol
level and serum adrenocorticotropic hormone (ACTH). The risk of developing diabetes mellitus for
schizophrenic patients first degree relatives is high, suggesting a possible genetic association
between diabetes mellitus and schizophrenia [34].

The metabolic syndrome and the neurocognitive deficit for patients with schizophrenia
Alongside with negative symptomatology, atypical antipsychotics have a limited effect over the
neurocognitive deficit; currently, sustained efforts are made in order to find optimal solutions for
improving cognitive functions in schizophrenia.
Literature reported recently controversial results referring to the association between the metabolic
syndrome and neurocognitive functions of patients with schizophrenia. The study of this possible
association has major implications in the prognosis of these patients. Many components of the
metabolic syndrome are potentially changeable parameters so that the improvement of the
metabolic condition could represent a benefit not only for decreasing cardiovascular risk but also
for the neurocognitive deficit of these patients which is considered to be one of the most important
disability factors in schizophrenia.
Within the population without psychiatric disorders, there is evidence of the negative effect the
metabolic syndrome has on cognition, especially on verbal memory, processing speed, executive
functions both for the adult population and elders. The studies carried out in this domain
demonstrate the negative effect of the metabolic syndrome regarding cognition [33, 32]. The
components of the metabolic syndrome such as high blood pressure, hyperglycemia and obesity are
important factors involved in the pathogenesis of the dementia syndrome [35]. Diabetes mellitus has
been associated to the poor speed and poor efficiency of processing information [36].
The relationship between metabolic syndrome and cognitive functions in schizophrenia has been
studied for the past years, the results of these studies being controversial. Using the data for the
CATIE study, Meyer et al did not outline a statistically significant link between the metabolic
syndrome and cognitive deficit for patients with schizophrenia [37]. One explanation of this result
could be related to the fact that the methodology of this study considered the metabolic syndrome as
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a dichotomous variable; therefore the investigation of the relationship between the metabolic
syndrome and cognitive functions was not carried out. The cognitive functions can deteriorate
progressively with the increase of the number of fulfilled criteria and the evolving worsening of the
parameters composing the metabolic syndrome. Therefore, using continuous variables seems to be a
more adequate approach in investigating this relationship. In a study carried out by Dickinson et al,
compared to the patients who only have diabetes mellitus and to patients who only have
schizophrenia, the patients with diabetes mellitus and schizophrenia suffered more cognitive
deteriorations, especially on the processing speed level and visuospatial abilities [38].
Friedman et al investigated the relationship between high blood pressure and cognitive
performances, respectively the body mass index and cognitive function of schizophrenia patients.
The authors of this study described a significant negative effect of high blood pressure over verbal
memory. The negative but statistically insignificant effect over memory of the body mass index
higher than 25 was also described. The other components of the metabolic syndrome (cholesterol
and triglyceride blood level, hyperglycemia) were not included in the analysis [39].
Lindenmayer et al reported the results of a study carried out on 159 patients with schizophrenia.
The schizophrenic patients with metabolic syndrome obtained lower scores on the cognitive tests
assessing the processing speed, attention, work memory and cognitive functions compared to
patients without metabolic syndrome. The increased plasmatic level of HDL-Cholesterol, weight
circumference and hypertriglyceridemia were significantly correlated with attention deficit [40].
Boyer et al studied the relationship between the metabolic syndrome, inflammation and cognitive
function, considering the metabolic syndrome both a dichotomous variable and a continuous one.
The authors defined the severity of the metabolic syndrome proportionally with the number of
modified parameters. In the first model, considering the metabolic syndrome as a dichotomous
variable, the metabolic syndrome and inflammation (measured through C-reactive protein) did not
present a statistically significant correlation with the cognitive function. In the second model,
considering the metabolic syndrome as a continuous variable, the number of modified parameters
part of the metabolic syndrome was associated with lower cognitive performances (memory,
attention and flexibility). High serum levels of triglycerides and obesity were also associated with
low cognitive performances [41].
In a recent study, Boyer et al described a possible functional sublayer of the relationship between
the metabolic syndrome and cognitive function concerning schizophrenia patients, employing the
99Mtc-ECD-SPECT method. Schizophrenic patients with metabolic syndrome recorded low scores
on the attention, memory and executive function tests compared to patients without metabolic
syndrome, as opposed to the general population suffering from metabolic syndrome where a mild or
moderately homogeneous cognitive deterioration of all cognitive functions is present. The
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examination using imagine methods revealed a more emphasized hypoperfusion of the prefrontal
left orbital cortex for patients with metabolic syndrome compared to schizophrenic patients without
metabolic syndrome. Moreover, the severity of the hypoperfusion was correlated with the severity
of the metabolic syndrome, assessed depending on the number of fulfilled criteria included in the
metabolic syndrome. Hyperglycemia, hypertriglyceridemia and abdominal obesity, which are also
involved in atherosclerosis process, represent the most significantly associated parameters with low
cerebral perfusion and cognitive deficit. [42].

Conclusions
The metabolic syndrome and the cardiovascular risk factors have a high prevalence in
schizophrenia patients. Besides the fact that cardiovascular disorders are one of the most important
causes of death in these patients, metabolic changes represent one of the most important causes of
non-compliance and non-adherence to antipsychotic treatment.
The etiology of metabolic syndrome in schizophrenia is multifactorial and confounded factors
contribute to the development of physical and biochemical abnormalities due to this syndrome: lifestyle,
antipsychotic medication and mental disorder related issues, including negative symptomatology.
Neurocognitive deficit represents one of the disability causes of schizophrenic patients. Studies
made so far suggest an association between metabolic syndrome, especially certain components of
the metabolic syndrome, and the neurocognitive deficit of these patients. Longitudinal studies are
necessary in order to pinpoint this association and to assess the effect the treatment of the metabolic
syndrome has over these patients cognition.
There are limited studies which investigate the relationship between negative symptomatology and
metabolic syndrome in schizophrenia. Longitudinal studies are needed in order to assess this
relationship and to investigate the potential underlying mechanisms.
Somatic pathology often leads to high mortality in schizophrenia patients. In order to manage
prophylaxis and adequate multidisciplinary treatment and to provide these patients with a quality of
life similar to the general population, a more sophisticated understanding of mechanisms that
contribute to somatic pathology, especially cardiovascular risk factors, is mandatory.

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Romanian Journal of Psychopharmacology (2015) 15, 147-155

THE AGGRESSIVE CONDUCT IN PERSONS WITH


PERSONALITY DISORDERS AND FORENSIC CONSEQUENCES
Alexandra Bolos1*, Vasile Chirita2, Roxana Chirita1
1
University of Medicine and Pharmacy Gr. T. Popa Iasi, Romania
2
Institute of Psychiatry Socola Iasi, Romania

Abstract
The persons with a diagnostic of personality disorders usually reflect, by the
gravity and repetitively of some acts with forensic involvements, a special
type of criminological category described at offenders. Diagnostic criteria for
personality disorders imply also the evaluation of the discernment, which is a
medical criterion for responsibility. Forensic evaluation of these persons is
very difficult because they are less collaborative with the evaluator and they
are especially manipulative and dissimulative. Thus, this paper, tries to
present some clinical modalities of evaluation, focus on some specific clinical
situations, because clinical diagnostic had a limited value regarding
understanding and prediction of criminal behavior.
Keywords: personality disorders, aggressiveness, forensic evaluation.

The psychiatric disorders affect both the individuals life as such and their familys life. Of all the
clinical manifestations specific to each and every psychic disorder, the hardest to accept and tolerate
by the people around is aggressiveness, violence. If violence is a social phenomenon with aggressive
manifestations, aggressiveness is an ethologic and biological phenomenon with social manifestations,
expressing a reaction to an environment situation, a reaction of defense to the ambiance [1].
Along time, people have attempted to define the aggression term. Most definitions focused on the
idea that an aggressive behavior is any violent action against other persons, which involves any
intention of harming or injuring other persons and refers even to interference with other events that
precede or follow the act. Despite all these, this term is not specified as such and is not defined in
the new diagnosis manuals. The different types of aggression are classified first of all based on a
behavioral pattern [2]. Therefore, a category is represented by physical aggressiveness on ones
own person, and another category refers to aggressiveness towards other persons or objects. Many
types of behavior are considered aggressive, even if they do not involve physical injury, such as
verbal aggressiveness. Furthermore, aggressions are considered any coercion acts against another
person, the intimidation of other persons, which implies a series of psychosocial consequences. The
*Corespondence: Alexandra Bolos, Socola Institute of Psychiatry Iasi, Sos. Bucium 36, 700282 Iasi, Romania.
Tel.: +40744479885; e-mail: bolalexandra@gmail.com.
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importance of all these types of behaviors must not be underestimated and their effects on the social
status and self-esteem will be taken into account [3]. People can have thoughts or fantasies
containing aggressiveness elements, but any idea becomes an act only when a person loses control
over their thoughts. Despite all these, any condition determining the accentuation of impulsiveness,
in case voluntary control is lost, will lead to violent acts. These situations involve organic and toxic
states, anomalies of the psychomotor development, psychoses or stressful environmental and
psychosocial factors. Distinguishing between fantasy and the act itself is very important as,
according to international laws, the psychiatrist will have to warn the authorities and the potential
victims, when they attend a patient with psychiatric disorders and with a potential for violent acts.
Nevertheless, the existence of simple thoughts, ideas or fantasies, even the sadistic, criminal ones,
do not belong to this category [4].
The psychiatric disorders associated to aggressive manifestations are represented by affective
disorders, schizophrenia, cognitive disorders such as dementia, delirium, attention deficit
hyperactivity, mental retardation, personality disorders. Lately, the number of crimes committed by
different persons with psychiatric disorders is apparently increasing, but very few aspects related to
the aggressive manifestations seen as a symptom of psychiatric disorders are known [5]. The
aggressions committed by persons diagnosed with psychiatric disorders are directed, generally,
against people they know or family members, which indicates that these aggressive manifestations
are not discriminative. The risk of aggressive behavior is higher in the stages of exacerbation of the
symptom, and in cases with a sudden onset of the disorder. Also, very often, the aggressive
behavior is also associated to alcohol abuse. As regards the evolution of the psychiatric disorder, no
potential correlation with aggressive manifestations is known [6]. From the point of view of the
gender differentiation, it has been found that the predisposition to an aggressive behavior is higher
in males and especially for aggressions such as homicides, rape, and use of fire weapons. The
forensic-medical complications of these aggressive manifestations must be seen also from the
perspective of social implications of the psychiatric disorders [7].
The personality disorders, seen as disharmonic structures generating a conflict with the ambiance, is
an unbalance characterized by the maintenance of the knowledge functions, but with constant
instability as regards the projection of ethical-existential values. Typically, these psycho-behavioral
structure disharmonies regard the entire personality during the entire lifetime, and sometimes
through the gravity and incoercible repetition of certain medical-forensic acts they illustrated the
category criminological described usually in criminals. For all these personality disorders, there are
certain common traits, though they have a varied psychopathological typology, namely [8]:
Impulsivity and instinctive prevalence in motivating acts;
The absence of guilt, with vindictive potential of frustrations;
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Disorders and Forensic Consequences

The absence of empathy, of sensitiveness to the feelings of surrounding people;


Overrated egophilia and egocentricity often on the background of affective deficit and
narcissistic developments;
The lack of remorse as regards the imputable committed deeds, resulting in the incapacity of
learning from the life experience;
The decrease in or the lack of tolerance to frustrations with violence and aggressiveness
reactions;
The malignity of premeditation, often illustrated in the minute preparation of antisocial acts;
The lack of loyalty to ones own commitments;
Psychoplasticity expressing externalization of ones own emotions, through tattoos and selfinjury;
The decrease in self-control, the search for and acceptance of short-term pleasures;
The lack of anxieties related to ones own abnormalities or behavioral failures;
Inclination to perversion and sexopathy;
Misbehavioral reiteration and relapse.
The self-mutilating behavior has been distinguished from autolytic compulsion, because the
intentionality of the act is not the death wish, even if the possibility of lethality is not excluded. This
syndrome is called "deliberate self-harm", as the patients hurt themselves, without any help from
other persons and wound themselves leaving scars [9]. The tattoo represents one of the unspecific
forms of deviating conduct significant in the socio-psychological and psycho-pathological
characterization of the personality disorder. The question arose whether the tattoo has a
preponderantly socio-psychological or psychopathological significance. The emergence of this
phenomenon both in aberrant self-destructive behaviors as well as in hetero-destructive ones, often
with associated lesions, scarred by aggressive self-release determined many researches to consider
this form of behavior as unspecific, but significant in guiding investigations meant for
characterizing the individual personality[10].
Even from ancient times, the tattoo has been widely spread, especially in primitive populations,
having numerous significances, such as distinctive sign of collectivity, adhesion to different groups
or religious concepts. The data in the specialized literature highlight important differences between
the tattoos of primitive people, which have magic and ritual-related or therapeutic significances, and
the ones in modern society, when they have a preponderantly personal character and belong less to
closed deviating groups [11]. Many authors consider that the tattoo has a legal and psychological
importance, as it reveals both the personality and identity of the individual, as well as different
traits. Other authors consider that the tattoo is a specific communication way because of the
impoverishment of verbal communication, being frequently found in immature and disharmonic
personalities. Sometimes, there is a correlation between the affective deficit and the number of
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tattoos, therefore a larger number of tattoos expresses a higher affective deficit [12]. A tattoo can
express passiveness, psycho-affective immaturity with narcissistic fixation, but it can also have a
professional or traditional significance, as the sailors, or can be performed in certain contexts, such
as the military service, or appear in patients with different psychiatric disorders like schizophrenia,
mental retardation or affective disorders [13]. The tattoos are also found in adolescents with
behavioral disorders and affective deficits and with a high frequency in people from penitentiaries,
having a medical-forensic, criminological or psychopathologic significance [14]. From the medicalforensic perspective, self-mutilation is considered a particular form of simulation. To designate selfmutilation different terms are used, such as parasuicide, focal suicide or suicidal gestures. DSM V
includes these manifestations in the diagnosis categories and defines them by the non-suicidal term
self injury [15]. The term self-mutilation is used to designate acts of self-inducing pain, without any
suicidal intention. Lebenluft establishes a series of stages previous to the act itself, namely [16]:
The existence of the triggering phenomenon;
The emergence or escalade of a dysphoric state;
The mental anticipation of self-mutilation;
Self-mutilation itself;
Achieving a state of relief of the psychic tension in exchange for physical self-injury.
Taking into account all these aspects, we examined 40 subjects over 18 years old, men with
dysharmonically structured personalities. In these subjects, we found 249 tattoos, which mean an
average of 6.2 tattoos per subject. The drawings found were very varied and represented portraits of
women, men, snakes, vampires, dice, daggers etc. As regards the theme of the tattoos, it is
apparently less important than the interpersonal relations created starting from the tattooing as a
particular form of deviating behavior. The motivation of these tattoos was very varied, namely:
Imitation, most people had a tattoo made imitating other people, many times the imitation
being unconscious;
A form of manifestation of the love for close persons like mother, sister, brothers;
Revenge against the girlfriend or boyfriend that abandoned them or against the judge that
sentenced them;
Sexual obsessions, especially for the ones that began their sexual life early;
Religious reasons, the drawings represented saints or crosses, thus expressing their
innocence.
It has been found that along life there are two important moments when the first tattoos are made,
namely between 17 and 18 years, when adolescence ends, and at the age of 20, especially during the
military service. Thus, we found that 32.5% of the subjects had their first tattoo made between 14
and 16 years, 40% between 17 and 19 years, 22.5% between 20 and 24 years old and 5% when they
were 13. Most tattoos were made under the spur of the moment, without being premeditated. Under
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Disorders and Forensic Consequences

these circumstances, 57.5% of them want more tattoos, as they correspond to their current affective
state, and 42.5% want to remove them and regret having them made.
The presence of tattoos, both in case of aberrant self-destructive behaviors and of hetero-destructive
ones, often concomitant with associated scarred lesions of aggressive self-release determined many
researchers to consider this form of aggressive behavior as unspecific, but significant in guiding
their investigations for the individual personality characterization. Tattoos can be interpreted as a
manner of expression of intrapsychic conflicts for others to notice them [17].
The consumption of alcohol leads to an apparent homogenization of the personality, whose
common aspect is an intense affective regression, egocentrism, emotional lability, irritability,
aggressiveness and a mental attitude of negation and trivialisation of the consumption, as well as its
frequent association to other toxicomanias [18]. Hence, it will obviously and persistently become an
irreproachable behavior with quasi-constant aggressive potential. Subsequently, there will be
complications and social-familial implications, which will trigger not only physical and psychic
pain, but also an increase in promiscuity and financial problems. Besides these individuals, both
people from the close vicinity and the ones that become victims of the aggressiveness states or
traffic accidents will suffer [19].
Therefore, we noticed the clinical manifestations emerged in persons with different personality
disorders, to which acute alcohol intoxication added, who committed different crimes. 62 cases of
people with borderline personality disorders, 29 with dependent personality disorders, 44 with
histrionic personality disorders and 20 paranoid personality disorders have been studied. In
borderline personality disorders, the alcohol consumption, even in small doses, determines mood
oscillations, intense psychomotor agitation disproportionate as regards its determining factor. The
aggressive acts can be the consequence of the exacerbation of irritability and at the climax of this
state, sometimes a narrowing of the self-consciousness field can occur. The post-intoxication period
is accompanied by intense asthenia, on the background of which anxiety, explosive manifestations
and aggressive behavior appear. In histrionic personality disorders accompanied by acute alcohol
intoxication, the specific traits like demonstrativeness, superiority, theatricality, elementary
affective reactions, demonstrative suicide attempts, over-simulation are found more intense. In
dependent personality disorders, the alcohol consumption will emphasize the feeling of inferiority
associated to self-incrimination and crying easily. On this background, explosive manifestations
emerge and the inhibition mechanisms are reduced. Hence, aggressiveness is manifested against
close persons, followed by significant guilt. In paranoid personality disorders, the alcohol
consumption will determine the accentuation of the sense of suspicion and the overrating ideas will
reach much easier a pathological level up to delirious ideas. Ideas are generally about chase and
persecution, accompanied by psychomotor agitation determining aggressive manifestations.
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Alexandra Bolos et al.

In borderline personality disorder, psychopathy cannot resist temptations and affective insensitivity
reaches amoralities and structures its personality according to deviating models until it becomes a
dominant personality. The relational condition of individuals with personality disorders is difficult,
because of the belligerence they maintain with themselves and the others, because of the frequent
risk of criminal implications, which limits their possibility of integration or rehabilitation, without
canceling the capacity of self-direction and of understanding the interrelations that they develop.
The medical criteria of the diagnosis guides on this line the assessment of the psychic capacity or
discernment, as a medical criterion of responsibility.
The medical-forensic assessment of the individuals with personality disorders is very difficult as
until now no appropriate longitudinal or cross-situational studies have been conducted on this line,
because many times these individuals find it very difficult to collaborate with the assessor and are
rather manipulative and dissimulative [20].
In psychiatry, aggressiveness is discussed and researched better depending on the place it holds in
the pathological organization, the premeditation of the act and its consequences. The
psychopathological dimension of the clinical evaluation is comprehensive for the longitudinal study
of personality and the horizontal incidence study based on biomedical analysis, which is subject to
different variables of risks and psychobehavioral developments. From the genetic and ontological
point of view of the psychobehavioral organization, through research emphasis, we will explore the
relational character of the achievement of a psychopathological evolution [21]. From the cultural
point of view, all the personality models are based on character and behavior concepts
corresponding to social rules. The current model to which all references are made is the AngloSaxon, according to Eyseck, in 1990, who admits the co-variation pattern between personality traits
[22]. The multidimensional assessment of the personality based on the identification of the basic
dimensions of the personality is possible with the help of psychobiological models described by H.
Eysenck, McCare, Zuckerman and Cloninger, which are operated through dimensional personality
tests such as TPQ-tridimensional personality questionnaire, NEO-PI personality inventory, TCI
temperament and character inventory, KSP Karolina scales of personality [23].
The personality disorder diagnosis involves great responsibility both professionally and morally, as
the entire psychism is affected and due to the complexity of the reference to the personality
considered normal and to the disorders of axis I [15]. The definition of the belonging to certain
nosological category of personality disorder as well as to any subtype within the said category will
exclude the somatic causes and the involvement of toxic factors, and the temperamental and
character dimensions will be taken into account. Nevertheless, this diagnosis has a stigmatizing
character as a result of the negative semantic conditioning, given that only the maladaptive traits
and the behavior consequences on the people around are highlighted. Diagnosing a personality
disorder means taking into account that these psychiatric disorders are very little known by the
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Disorders and Forensic Consequences

community, which tolerates them, and that the patient is not aware of them [24]. Also the
temperamental traits are more stable than the character ones, which are conditioned especially
socioculturally. In many cases, the personality disorders have a mixed character generated by
different associated traits of different gravity levels as regards psychodynamics, being neurotic,
borderline or psychotic. Self-perception is well structured in personality disorders in cluster C, but it
is diffuse in the disorders in cluster A and cluster B, the skills of reality testing being either intact or
partly or intermittently affected [25]. They exteriorize as persistent adaptive difficulties masked by
the intellectual level, social, cultural or professional factors and the entourages tolerance.
Therefore, the personality disorder diagnosis becomes a staged diagnosis depending on the intensity
of the behavioral manifestations, such as the patients impulsive attitudes, suspiciousness or
passivity. The situations when these patients are compensated or have a medium adaptability level
must also be highlighted. Sometimes, the reference to the therapeutic offer, namely refuse,
ambivalence, receptiveness, can also depend upon the presence of close persons who will ease the
dialogue with the interviewer [26]. The first contact with the patient can take place based on
questions such as what can I do for you?, what can I do for you now?. The assessors personality
and even their scientific education and gender can represent valuable references for the
precociousness and accuracy of the diagnosis. The social support network can represent another
important element of diagnosis together with the economic factors [27].
Personality disorders are an important field in psychopathology and sociology, as they are entities
different as regards quality from the rest of the psychiatric nosologic categories and different as
regards quantity from the normal personalities, which are structures conditioned by several factors,
which affect the interpersonal relations and the reference to the community values [28]. They can
also be etiologic factors for certain psychiatric disorders and can have the same determinism as
theirs, especially when they belong to the same spectrum. Any attempt of classification can have a
touch of arbitrary also due to the mutual interconditioning, with the disharmonic behavior having
negative repercussions on the individual and community, but also the other way around, different
socioeconomic aspects can influence maladaptive behavior [29].
The personality disorder diagnosis is heterogeneous as individuals with the same personality
disorder can have variations as regards the criteria used for diagnosis. Therefore, Hare considers
that not all those diagnosed with an antisocial personality disorder have prototypical characteristics
of rudeness, seduction, lack of affective resonance [30]. Lynam asserts that the successful patient
with personality disorder versus the failed one means competence and involvement versus
irresponsibility, negligence, lack of involvement [5].
Acknowledgments and disclosure
The authors declare that they have no potential conflicts of interest to disclose.
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Alexandra Bolos et al.

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19. Pirozynski T. Psihiatria in societate. Ed Psihomnia, Iasi.1995.


20. Rietdijk E. et all. Predicting selfdamiging and suicidal behaviours in female borderline
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155

Romanian Journal of Psychopharmacology (2015) 15, 156-162

PREDISPOSING AND PRECIPITATING FACTORS


IN REFRACTORY DEPRESSION
Ghenadie Carausu1*, Alina Crasmari2, Eugenia Sinita3
1
State University of Medicine and Pharmacy Nicolae Testemitanu,
Chisinau, Republic of Moldova
2
Psychiatric Clinical Hospital, Chisinau, Republic of Moldova
3
National Center of Mental Health, Chisinau, Republic of Moldova

Abstract
Introduction: Currently, depressive disorders incidence presents a significant
increase in population. In the following decades this pathology will place first
in the world, surpassing cardiovascular diseases and trauma. Resistant
depressions are a major public health problem, with an expansion in all walks
of life, having impact on patient functionality with significant deterioration in
the quality of life. The aim of the present study was to evaluate predisposing
and precipitating factors in setting of resistant depression.
Method: The study was conducted on a group of 612 patients with resistant
depression, with an observation period of 30.25 0.20 inpatient days.
Quantification of depression was performed with Montgomery-sberg
Depression Rating Scale and the Beck Depression Inventory. Data
investigations were considered significant at p<0.05.
Results: Premorbid peculiarities of patients polymorph, and the presence of
family tension conditions caused by lack of husband, psychological noncompliance of spouses, sexual disharmony, open opposition, as insoluble
character of material and existential problems (lack of proper housing,
insufficient salary) have unfavorable dynamics contributed to the
installation of the disease. But such states to become pathogenic as it took a
combination variable between childhood educational experiences and
actual traumatic events.
Conclusions: The premorbid personality structure of patients during different
traits was present, with the prevalence of sensitivity, emotional liability,
anxiety and introversion. The largest group of subjects showed abandonment,
separation, divorce or death, reduced emotional support, sense of loneliness
and failure of personal life.
Keywords: refractory depression, predisposing factors, precipitating factors.

*Correspondence: Ghenadie Cruu, Tel: + 37369373670; e-mail: drcarausu@yahoo.com.


156

Predisposing and Precipitating Factors


in Refractory Depression

Introduction
Nowadays is noted a significant increase of depressive disorders in the population [1]. The number
of people affected will increase considerably in the coming years so that depression will record
most social costs (the number of years of life lost because of premature death or severe disability
caused by the disease) of all other pathologies [2]. Resistant depression is a particular field in the
depressive disorders. The burden of this pathology on the individual himself, his family and society,
is the rationale for considering refractory depression as a major public health concern [3, 4]. Among
the reasons which cause these diseases limits therapy were noted premorbid characterological
peculiarities of the individual, unfavorable family microclimate etc. [5, 6]. The aim of the thesis
was to study predisposing and precipitating factors in setting resistant depression.

Material and method


There were enrolled 612 patients in the study, 491 (80.23%) women and 121 (19.77%) men with
major depressive episodes resistant to treatment, hospitalized in Clinical Psychiatric Hospital,
Chisinau. The patients were included in the study based on inclusion and exclusion criteria. The
inclusion criteria were: male or female patients, age between 18 and 69 years; patients who met the
criteria for recurrent depressive disorder after ICD-10; subjects who received treatment with
antidepressants administered sequentially with therapeutic dose, lasting for at least four weeks for
each prior visit inclusion, which had unsuccessfully clinical response. The exclusion criteria:
patients age under 18 and over 69 years; subjects with a range of medical conditions associated
with severe and acute stage of relapse. 170 patients (27.78%) were classified as recurrent depressive
disorder, current episode mild (F33.1), 276 subjects (45.10%) - in the category of recurrent
depressive disorder, current episode severe without psychotic symptoms (F33.2) and the remaining
166 patients (27.12%) developed severe depression with psychotic symptoms intensity (F33.3).
The inhabitants of the cities were 416 subjects, while of villages 196 patients. The average age
of patients was 47.29 0.91 years and mean disease duration of 13.25 0.72 years. Share
married at the time of admission of patients was 54.08%, 45.92% remaining being divorced, and
unmarried or widowed.
Quantification of depression was performed with Montgomery-sberg Depression Rating Scale and
the Beck Depression Inventory. The clinical psychopathological examination of patients was
performed using a questionnaire that included comprehensive evaluation of various factors
predisposing and precipitating in the disease. The investigation was oriented on subjects
investigations peculiarities personalities, their emotional moods, interpersonal relationships, how to
behave particularities of the individual, personal level of aspirations, but other events, which
occurred shortly before disease onset: professional difficulties mourning rupture sentimental family
157

Ghenadie Carausu et al.

problems - separation, divorce, breakup, abandonment. Data investigations were considered


significant at p<0.05.

Results
No personality structure confers invulnerability to human refractory depression. The addicts are
more vulnerable to events in the relational and the relatively autonomous - more sensitive to events
that involve the subject in a personal achievement [7]. Our data indicate that premorbid
characterological peculiarities of the person influenced the formation of unfavorable dynamics of
depressive episodes. These individuals were predominantly sharp, polymorph, formed especially in
childhood and adolescence, often products of a tense family environment, conflict.
Data dynamics score as assessment scales during inpatient observation (30.25 0.20 days) shows
that of the 612 (100%) enrolled patients - 545 (89.1%) of subjects had positive results in treatment:
remission - 29 (4.7%) patients and partial remission - 516 (84.3) subjects - group I and 67 (10.9%)
patients were noted negative results (no remission) - group II. Thus, according to the groups
studied, the distribution of patients according to the following denotes the premorbid personality
traits (Table 1).
Table 1. Characteristics of subjects according to premorbid personality traits
(*p>0.05; ** p<0.05)
Character
Harmonious
Rigidity
Scrupulosity
Anxiety
Sensitivity
Trends for forming obsessions
Emotional lability
Hypochondriasis
Introversion
Autodramatization

Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No

Group I
N
%
44
8,07
501
91,93
65
11,93
480
88,07
120
22,02
425
77,98
130
23,85
415
76,15
229
42,02
316
57,98
100
18,35
445
81,65
185
33,94
360
66,06
125
22,94
420
77,06
129
23,67
416
76,33
115
21,10
430
78,90

Group II
N
%
3
4,48
64
95,52
10
14,93
57
85,07
21
31,34
46
68,66
24
35,82
43
64,18
26
38,81
41
61,19
14
20,90
53
79,10
25
37,31
42
62,69
20
29,85
47
70,15
23
34,33
44
65,67
12
17,91
55
82,09

1,09

0,50

2,93

4,54

**

0,25

0,26

0,30

1,58

3,63

**

0,37

The graphic presentation of the subjects according to the premorbid personality traits in both groups
are shown in Figures 1 and 2.
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Predisposing and Precipitating Factors


in Refractory Depression

Figure 1. Premorbid personality traits in group I


Legend: 1. Harmonious; 2. Rigidity; 3. Scrupulosity; 4. Anxiety; 5. Sensitivity; 6. Trends for forming
obsessions; 7. Emotional lability; 8. Hypochondriasis; 9. Introversion; 10. Autodramatization.

Figure 2. Premorbid personality traits in group II


Legend: 1. Harmonious; 2. Rigidity; 3. Scrupulosity; 4. Anxiety; 5. Sensitivity; 6. Trends for forming
obsessions; 7. Emotional lability; 8. Hypochondriasis; 9. Introversion; 10. Autodramatization.

The socio-economic and family backgrounds are factors closely associated with the development of
depressive disorders [8]. Regarding the living conditions, we can mention that more than half of
enrolled patients - 340 (55.56%) declared better living conditions, while others - 272 (44.44%)
mention indigence. Family microclimate in turn exert significant influences on installing a refractory
depression, determined that the risk of developing a depressive state resistance is higher in singles,
lonely, divorced, childless people, those educated in incomplete families orphanages [9, 10]. Other
conditions like not sharing emotions, low emotional support, lack of intimate relationships, hostile
attitude towards children, childcare up to 14 years, poor housing, jealousy, venereal disease, lack of
trust, physical aggression, loneliness, failure of personal life, emigration of partner, abandonment,
separation, produce some instability with a direct repercussion on the family [11]. In these cases,
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Ghenadie Carausu et al.

the subjects transferred responsibility for developing situation morbid significance of the spouses.
Mitigating of traumatic circumstances marginally influences to the improvement of the patient's
condition and worsening often occurs even under neutral factors present no pathogenic
significance (minor offenses, worries, petty conflicts etc.).
The distribution of patients in relation to situations created in their own family is reflected in Table 2.
Table 2. Characteristic of situations created in own family
Conditions
Not sharing emotions
Low emotional support
Lack of intimate relationships
Hostile attitude towards
children
Caring for children up to 14
years
Unsatisfactory residence
Lack of trust relationship
Physical aggression
Feeling of loneliness, failure
of personal life
Emigration of partner
Abandonment, separation,
divorce, death

Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No

Group I
N
%
96
17,61
449
82,39
149
27,34
396
72,66
123
22,57
422
77,43
67
12,29
478
87,71
72
13,21
473
86,79
53
9,72
492
90,28
123
22,57
422
77,43
65
11,93
480
88,07
126
23,12
419
76,88
99
18,17
446
81,83
219
40,18
326
59,82

Group II
N
%
15
22,39
52
77,61
20
29,85
47
70,15
18
26,87
49
73,13
11
16,42
56
83,58
9
13,43
58
86,57
5
7,46
62
92,54
19
28,36
48
71,64
6
8,96
61
91,04
17
25,37
50
74,63
12
17,91
55
82,09
28
41,79
39
58,21

0,92

0,19

0,62

0,91

0,00

0,36

1,12

0,51

0,17

0,00

0,06

Legend: * - p>0.05

Graphical representation of the situations of their own family in the groups studies is shown in
Figures 3 and 4.
According to the presented data, the largest group of subjects experienced abandonment, separation,
divorce, death, noted in the own family: group I - 219 (40.18%) cases, group II - 28 (41.79%); low
emotional support: group I - 149 (27.34%) cases, group II - 20 (29.85%); feeling of loneliness,
failure of personal life: group I - 126 (23.12%) cases, group II - 17 (25.37%) (p>0.05).

Discussion
Resistant depression occurs mostly in a sensitivity of personality. This complex personality
structure and the presence of stressful conditions of personal family environment lead to a
development of unfavorable psychopathological symptoms. Thus, we can say that refractory
depression is often linked to instability of patients personal life (marriage disharmony, bad
relationship with spouse, but also insoluble character of material and existential problems). But for
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Predisposing and Precipitating Factors


in Refractory Depression

such states to become pathogenic, it requires a variable joint between childhood educational
experiences and actual traumatic events.

Figure 3. The structure of the situations in families of the group II


Legend: 1. Not sharing emotions; 2. Low emotional support; 3. Lack of intimate relationships;
4. Hostile attitude towards children; 5. Caring for children up to 14 years; 6. Unsatisfactory residence;
7. Lack of trust relationship; 8. Physical aggression; 9. Feeling of loneliness, failure of personal life;
10. Emigration of partner; 11. Abandonment, separation, divorce, death.

Figure 4. The structure of the situations in families of the group II


Legend: 1. Not sharing emotions; 2. Low emotional support; 3. Lack of intimate relationships;
4. Hostile attitude towards children; 5. Caring for children up to 14 years; 6. Unsatisfactory residence;
7. Lack of trust relationship; 8. Physical aggression; 9. Feeling of loneliness, failure of personal life;
10. Emigration of partner; 11. Abandonment, separation, divorce, death.

Conclusions
In premorbid patients there were identified different traits, but prevailed the following: the
sensitivity: group I - 229 (42.02%) cases, group II - 26 (38.81%); emotional liability: group I - 185
(33.94%) cases, group II - 25 (37.31%); anxiety: group I - 130 (23.85%) cases, group II - 24
(35.82%); introversion: group I - 129 (23.67%) cases, group II - 23 (34.33%). Data show that in
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Ghenadie Carausu et al.

own family the largest group of subjects had suffered situations of abandonment, separation,
divorce, death: group I - 219 (40.18%) cases, group II - 28 (41.79%), as well as low emotional
support: group I - 149 (27.34%) cases, group II - 20 (29.85%); feeling of loneliness, failure of
personal life: group I - 126 (23.12%) cases, group II - 17 (25.37%).

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162

Romanian Journal of Psychopharmacology (2015) 15, 163-181

RELATIONSHIP BETWEEN CANNABIS AND PSYCHOSIS:


CHALLENGES AND CONTROVERSIES
El Hadi Zerdazi1, Maria Ladea2, Andrei Szke1,3,4,5*, Ion Udristoiu6,
Marion Leboyer1,3,4,5, Franck Schrhoff1,3,4,5, Aziz Ferchiou1,3,4,5
1
AP-HP, DHU PePSY, Groupe Hospitalier "Mondor",
Ple de Psychiatrie et dAddictologie, Crteil, 94000, France
2
University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
3
INSERM (French National Institute of Health and Medical Research),
U955, team 15, Crteil, 94000, France
4
UPEC, University Paris-Est, Facult de Mdecine, Crteil, 94000, France
5
Fondation FondaMental, Crteil, 94000, France
6
University of Medicine and Pharmacy Craiova, Romania

Abstract
Converging data support the association between cannabis consumption and
schizophrenia, and many different hypotheses could explain the association,
even though a link of causality is still debated. Part of these uncertainties is
due to schizophrenia itself, a chronic and severe disease, with a long
prodromal phase, frequent comorbid conditions and the need of
psychopharmacological treatment. Thus studying cannabis in nonschizophrenic psychotic spectrum disorders may help understanding this
association and avoid confounding factors inherent to schizophrenia.
The study of cannabis-induced psychosis could be of special interest, because a
high incidence of developing schizophrenia, in such clinical forms, was
observed. Another interesting domain is the study of cannabis consumption in
attenuated forms of psychosis, because it avoids some of the confounding factors,
especially medication, and allows enlarging samples to general population.
Based on the available data, the mechanism that seems to explain better this
association is the neurotoxic effect of cannabis that depends on its use within
a period of vulnerability (i.e. adolescence) and probably on a cumulative
exposure base.
Even if a causal relationship seems probable, before an efficient prevention of
psychosis by preventing cannabis consumption could be designed, more
research is needed (e.g. to define the populations at risk, to find efficient
methods for preventing cannabis consumption etc.)
Keywords: cannabis, psychosis.

*Correspondence: Andrei Szke, e-mail: andrei.szoke@sfr.fr.


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1. Introduction
Cannabis is the most frequently used illegal drug with a prevalence estimated between 2.7% and
4.9% of worldwide adult population aged 15-64 years. In vulnerable subjects, cannabis intoxication
can cause psychotic manifestations. On the other hand, epidemiological data repeatedly found that,
among patients with schizophrenia - the most common and severe psychosis about one-quarter of
them have a lifetime cannabis use disorder. Based on this knowledge, given the severe individual
and social consequences of schizophrenia, and the high prevalence of cannabis consumption, the
link between cannabis and schizophrenia has generated a lot of interest and research.
Longitudinal studies showed that cannabis could have a causal effect leading to an increased risk of
developing schizophrenia, with a pooled adjusted odds ratio =1.41, 95% CI 1.20-1.65. This risk was
larger in individuals using cannabis most frequently and in higher doses [1]. Several studies have
explored the effect of cannabis use on the course of schizophrenia and found that cannabis was
associated with increased number and duration of hospitalizations, a longer first hospitalization and
poorer adherence to treatment. On the other hand, previous studies indicated that cannabis use was
associated with abrupt onset and more positive symptoms than non-cannabis schizophrenic users,
which is usually considered of better prognosis, especially regarding the response to treatment of a
psychotic episode. It has to be reminded that many studies had certain limitations, such as lack of
control of baseline severity.
In conclusion, the link between schizophrenia and cannabis use is very complex. Some studies
suggested that the association between cannabis and psychotic symptoms in schizophrenia was
bidirectional: cannabis was associated with a worsened course of psychotic symptoms, but
psychotic symptoms also increased cannabis use.
Part of the difficulties in reaching a definite conclusion concerning a causal role of cannabis in the
aetiology of schizophrenia are inherent to schizophrenia, e.g. the presence of multiple confounding
factors (medication, comorbid psychiatric symptoms, hospitalization etc.), a relatively low
prevalence and difficulty in ascertaining the onset of the disorder (most often onset is insidious with
a long prodromal phase, memory biases, etc.). The latter point makes it difficult to define the
temporal relationship between cannabis consumption and onset of schizophrenia.
To better understand the association between cannabis and psychosis, and avoid these difficulties,
the study of the relationship between cannabis consumption and other psychotic spectrum disorders
has been advocated. This approach is based on the assumption that the way in which cannabis
causes psychosis is similar regardless of the specific disorder, and could benefit from the fact that
some of the confounding factors (medication, comorbid psychiatric symptoms, hospitalization,
institutionalization, etc) associated with schizophrenia may not be present in these disorders.
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A better understanding of these mechanisms will help not only to better understand the
pathophysiology of the disease but will also lead to the improvement of treatment strategies.
The aim of this article is to summarize the current knowledge of the relationship between cannabis
and psychosis, trying to answer to the following questions:
1) Can the study of cannabis consumption in milder phenotypes of the psychosis spectrum help
to better understand this association?
2) What are currently the different pathophysiological hypotheses that explain this association?
3) And finally, which role could play cessation of cannabis consumption in preventing
psychosis?

2. Cannabis in the schizophrenic spectrum and other psychotic disorders


From the first descriptions, psychotic symptoms and cannabis consumption were associated, and a
large literature data studying the link between cannabis and psychosis has been published.
Psychosis is a polysemic term having various meanings based on theoretical and, sometimes,
historical considerations. In this article, we use the term in its narrow, descriptive definition i.e. the
presence of delusions and/or hallucinations.
This includes psychotic disorders (according to the Diagnostic and statistical manual of mental
disorders: DSM-5) for which delusions and/or hallucinations are primary, defining features;
disorders in which these symptoms are present in a full form but considered secondary to toxic (e.g.
cannabis) or affective causes and, finally, schizotypy in which these symptoms, although defining
features, are present in an attenuated form.
2.1. Cannabis induced (toxic) psychosis
Acute cannabis induced psychosis refers to the occurrence of psychotic symptoms following
cannabis use, which are clinically significant with functional consequences requiring in most cases
antipsychotic intervention and even hospitalization. They are estimated between 0.03 and 1.1 of
the subjects exposed to cannabis [2] and 2.7 per 100 000 person-year of general population [3].
In the literature there is no consensus regarding the definition of cannabis induced psychotic disorder
(CIPD). Most authors that studied cannabis induced psychoses distinguish two broad categories of
psychoses: the toxic, acute, transient psychosis (corresponding to the Substance Induced Psychotic
Disorder of the DSM 5) and "functional" or "primary" psychoses for which the cannabis is thought to
reveal pre-existing psychosis vulnerability, having mainly the role of a precipitating factor.
A central question is how to differentiate the onset between the two types of psychosis which could
have important consequences on the treatment strategy, e.g. limited prescription of antipsychotics
until symptomatic remission in case of CIPD or maintained medication after remission in case of
primary psychosis.
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Different approaches have been proposed to differentiate these two types of disorders.
Some authors proposed to use clinical clues as the presence of delirium symptoms (sensorium
alteration, disorientation) during acute episodes in order to differentiate the CIPD from the
functional (primary) cannabis psychosis.
Other authors used an empirical approach to identify clinical characteristics that could differentiate
between the two disorders. These longitudinal studies used a structured interview specifically
designed to differentiate substance induced and primary psychiatric disorders. As a whole, they
suggested that the best predictive variables are: the temporal sequence (onset of cannabis use
preceding the psychosis), greater overall PANSS scores, family history, poorer premorbid
adjustment and poorer insight (in favor of primary psychosis), and visual hallucinations (in favor of
CIPD). Rubio et al. [4] confirmed most of these findings and also found subjects with cannabis
induced psychosis to be older, to use more cannabis and to exhibit more often depressive and
anxious symptoms.
Finally, some studies proposed to assess the potential endophenotypes that characterize subjects
with psychosis to help distinguish between transient CIPD and schizophrenia.

For example,

Morales-Munoz et al. [5] compared the prepulse inhibition (PPI) of the startle reflex between
different patients groups, including CIPD, schizophrenic patients with a past history of cannabis,
and controls. At maximum inhibition (prepulse-pulse interval of 120 ms) CIPD patients showed an
intermediate PPI deficit, which is lower than controls but higher than patients with schizophrenia.
However, the distinction could be less important in the long run. Longitudinal studies among
inpatients admitted for CIPD found that up to 46 % of them met the criteria of schizophrenia at the
end of a follow up of 8 years [6]. Available data suggest that this proportion increases with the
duration of the follow up until reaching a plateau. For example, Caton et al. found that after one
year, 25 % of the patients present a diagnosis of schizophrenic disorder, this proportion increase to
44,5 % after 3 years, the last proportion being similar to the one that was found after 8 years [3,6,7].
When including other psychosis spectrum disorders, the percentage reaches, after 3 years, 77% [3].
Given the clinical similarities and the high percentage of transition to "functional" psychoses, some
researchers proposed a continuum between CIPD (being less severe and transient when cannabis is
discontinued) and functional (chronic) psychosis.
Studying cannabis psychoses appears then to be of a major interest because of the high incidence of
cases that later develop schizophrenia. On another level, human models of cannabis-induced
psychosis are central to understanding the role of endocannabinoid systems in schizophrenia.

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2.2. Cannabis in Bipolar disorders


Psychotic symptoms during episodes of mania and depression are common in the course of
bipolar disorder.
A relationship between cannabis use and BPD has been suggested. However, to date, definite
evidence is lacking (there are not enough studies and the lack of longitudinal studies makes reverse
causality possible).
There is some evidence suggestive (but by no means definite) of earlier onset of BPD in subjects
that used cannabis. This link has been found to be limited to manic and psychotic (but not purely
depressive) episodes and to be dose-dependent [8,9]. There are also studies that found an increased
relative risk for BPD, and of subsequent manic (but not depressive) episodes. For the association of
cannabis use and BPD with psychotic symptoms, which is of interest for our review, there are few
data available [10].
In a longitudinal study of young subjects at genetic risk for BPD, Duffy et al, [11] found that
cannabis use increased the risk of both major affective disorder and psychotic symptoms.
Thus, the study of bipolar disorders has been less helpful in understanding the association between
cannabis and psychosis partly because of the lack of data in the literature, and partly because of the
fact that BP disorders could suffer from the same biases than in schizophrenia (long course of
illness, on-going medication, etc.).
2.3. Cannabis and attenuated/isolated psychotic symptoms
2.3.1. Cannabis and schizotypy
Schizotypy is characterized by the presence of psychological traits similar to symptoms of
schizophrenia but in an attenuated form.
There are two main theoretical views on schizotypy [12]: a categorical model that led to the definition
of schizotypal personality disorder as a pathological entity clearly separated from psychological
normality (health) and a dimensional model of psychometric schizotypy supposing a quantitative
variation of one or several schizotypal dimensions on a continuum across health and pathology.
In a prospective longitudinal study, Anglin et al. [13] demonstrated that the early (i.e. before 14
years old) use of cannabis, strongly predicted the presence of schizotypal personality disorder
(SPD) symptoms in adulthood. This effect was independent of adolescent SPD symptoms. Despite
some limitations (e.g. low prevalence of SPD in this study), this result suggested that cannabis
might contribute to the etiopathogenesis of schizophrenia-related symptoms.
In a large population-based study, Davis et al. [14] found that the prevalence of schizotypal
personality disorder increased significantly with greater cannabis use in a dose-dependent manner
(lifetime cannabis use, abuse and dependence). However, the cross-sectional design of the study
limits the interpretations regarding causality.
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Psychometric schizotypy has also been studied in relation to cannabis consumption. In a recent
meta-analysis of the 27 studies published to date, we showed that cannabis use is associated with
increased scores of psychometric schizotypy, especially the positive dimension. However, the lack
of longitudinal studies exploring the link between cannabis and psychometric schizotypy prevented
us from drawing any conclusion concerning the causal direction of this association [15].
2.3.2. Psychotic-like experiences
Psychotic-like experiences (PLE) refer to the presence of psychotic symptoms (delusions and/or
hallucinations) in the absence of other characteristics that are seen in the clinical category of
psychosis. These isolated symptoms are rather frequent in the general population with an estimated
prevalence of 7.2% and transient in nearly 80% of cases [16]. Globally, frequency of PLE decreases
from 6% in childhood and adolescence (11-18 years) to 3 % at adulthood (19 26 years) [17]. In
the literature, the course of PLE can have three distinct trajectories: increasing (and even evolution
to a psychotic disorder), decreasing (or even disappearance) or stable. Hanssen and al. [18]
described among 79 adults with PLE followed for 2 years, that 14 % of them presented a psychotic
disorder, 54 % didnt report PLE at follow up, and 32 % showed stability. Furthermore, PLE are
considered as a risk factor for schizophrenia; their presence at 11 years increases the risk by 16 fold
to fulfil schizophrenia diagnosis at 26 years [19].
Studies of PLE in the community showed that cannabis consumption is associated with PLE
presence, and more so for a younger age of onset of cannabis consumption and a higher frequency
use [20,21,22]. These studies, in different populations, used the same self-report instrument: The
Community assessment of psychic experiences (CAPE) and found convergent results.
In the meta-analysis by Linscott & van Os [16], cannabis increased 2.5 times the prevalence of
psychotic experiences. These data suggest two hypotheses: those with PLE may present a risk factor
for cannabis use, or cannabis use may increase the incidence of PLE. Some studies are in favour of
the later hypothesis; indeed, after controlling for psychotic symptoms during childhood, predating
cannabis use, there is still an increased risk for psychotic manifestations associated with cannabis
consumption in adulthood. Nevertheless, Mackie and al. [23] found divergent results, which are
more compatible with the former hypothesis. In a cohort of 409 adolescents with a higher median
score of the Substance Use Risk Personality Scale (SURPS) [24] which assesses four personality
risk factor for SUD (Substance Use Disorder), cannabis use did not predict increase in the PLE
score after 6 months (OR : 1.2 [0.3-4.2]). But on the other hand, in the persistent and increased PLE
groups, cannabis use rate raised significantly during the first 6 months follow up and remained
stable for the subsequent 18 months. The limitation of this study is that it concerns basically a
population at risk for SUD, and probably among these individuals PLE led to a higher consumption,
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in order to alleviate their symptoms. This may suggest that the direction of the relationship between
cannabis and PLE differs among different populations, and probably changes across time evolution
of the symptoms and/or the substance use.
Another interesting concern is the psychotomimetic symptoms evolution during and after cannabis
intoxication. Mason and al. [25], using a self-rating scale: the Psychotomimetic States Inventory
(PSI) among 140 cannabis users in a naturalistic study, found an elevation in psychotomimetic
symptoms during intoxication, which was even more pronounced among highly psychosis-prone
individuals, according to their SPQ score. Nevertheless, the scale used does not explore only PLE.
The same results were found by Stirling and al. [26] in a multicentric study using another self-rating
scale: The Cannabis Experience Questionnaire (CEQ) which includes a PLE subscale. Indeed, high
schizotypy basal score predicts high PLE rating after cannabis administration, especially among the
current than the past users. Furthermore, after cannabis cessation, Baskak and al. [27] found a
decrease in sub-psychotic symptoms assessed by the Schizotypal Personality Questionnaire (SPQ)
positive score which was proportional to cannabis cessation duration.
Our principal remark concerns PLE assessment - the instruments used to assess PLE are
heterogeneous and sometimes not specific. On one hand, scales assessing schizotypy like the SPQ
are used to assess PLE, and on the other hand, some PLE scales, like the CAPE, have items similar
with those used to assess schizotypy (e.g. SPQ).
In summary, studies of cannabis in milder or attenuated forms of psychosis allowed to enlarge
samples to general population, avoiding confounding factors seen in psychotic episodes (i.e.
medication, hospitalization, comorbidities etc). Nevertheless, in some studies, the distinction
between PLE and schizoptypy is not clear.
2.4. Cannabis and psychosis in subjects at genetic risk for psychosis
The study of cannabis influence regarding the risk for developing psychosis in subjects at genetic
risk for schizophrenia could help elucidate mechanisms by which cannabis leads to psychosis, in
particular the hypothesis of a gene and environment (i.e. cannabis) interaction. Few studies explored
the relationship between cannabis and psychosis in relatives of schizophrenic subjects and they
have revealed conflicting results.
Studies in relatives of schizophrenic patients found that the genetic risk for schizophrenia is
associated with a higher sensitivity to the psychotomimetic effects of cannabis. In Arendt et al. [3]
study, children of schizophrenic mothers had an increased risk of developing cannabis-induced
psychosis. Results of the Genetic Risk and OUtcome of Psychosis (GROUP) [28] study suggested
that unaffected siblings of psychotic patients displayed higher rates of cannabis use and more
sensitivity to the psychotomimetic effects of cannabis than controls.
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In contrast, studies that compared the familial risk for psychosis between groups of patients with
and without cannabis use, lead to conflicting results. McGuire et al. [29] found a higher morbid risk
of psychosis, particularly for schizophrenia, in relatives of subjects that used cannabis. Other studies
did not found a difference of genetic risk (family risk) when groups of patients using cannabis were
compared with those that did not use cannabis. A more recent controlled family study suggested
that the risk for developing schizophrenia is associated to family history of the illness regardless of
cannabis use [30]. Finally, in a slightly different type of study, Veling et al. [31] showed that
genetic predisposition for schizophrenia does not predict cannabis use (i.e. there are different
genetic influences for the 2 disorders).
Thus, as a whole, convergent results suggest that people at genetic risk of schizophrenia are more
prone to experiencing psychotomimetic effects of cannabis, which in itself can be considered as an
endophenotype for schizophrenia. In addition to its association with schizophrenia, cannabis seems
to be linked to a more wide definition of the psychosis spectrum. On the other side, studies are less
consensual concerning a higher genetic predisposition to psychosis among cannabis user relatives.
This could be explained by the fact that cannabis use initiation is under environmental influence but
transition to dependence involves more genetic factors. Refining the phenotype cannabis use to
cannabis dependence could be more interesting to study in this context.
3. Association between cannabis and psychosis: neurobiology and hypotheses
3.1. Cannabis and the endocannabinoid system
Among the cannabis genus, two (of the three) species are known for their psychotropic effects:
Cannabis sativa and Cannabis indica. Most of the strains actually consumed are obtained by
hybridation from them. Among more than eighty identified phytocannabinoids, THC (Delta-9Tetrahydrocannabinol) is the most psychoactive compound. Administration of THC induces positive
psychotic symptoms in both healthy individuals and those with schizophrenia. Others cannabinoids
like cannabinol (CBN) and cannabichromene (CBC) may have less potent psychotropic effects.
Recently, it has been suggested that cannabidiol (CBD) could moderate the psychotomimetic effects
of THC and alleviate the psychotic symptoms in schizophrenia.
From a medical point of view, it is more pertinent to refer to chemotype based taxonomy to
classify the strains. This classification is based on the ratio THC/CBD which differentiate the
drug-type with the higher ratio from the fiber-type. One of the problems in studying cannabis
consumption is that the substance called cannabis in naturalistic studies includes drugs with
different levels of cannabinoids. In addition, there is an emerging consumption of synthetic
cannabinoids with more potent effects than THC in young people.
It was long believed that the psychoactive effect of THC occurs via a non-specific mechanism of
diffusion across the cell membrane because of its lipophilic properties. However, in early 90s, the
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first cannabinoid receptor, the CB1, has been identified in rat and human brain. Its a G proteincoupled receptor distributed primarily in the central nervous system (the basal ganglia, the
hippocampus and the cerebellum). Other endocannabinoid receptors (CB2, CB3) and endogenous
ligands (Anandamide and 2-ArachidonoylGlycerol) were identified, but their involvement in the
psychoactive effects of cannabis is still debated.
The CB1 receptor is localized at the pre-synaptic extremity of excitatory and inhibitory neurons,
where its activation leads to a decrease in the neurotransmitter release. Indeed, endocannabinoid
transmission is anti-sense and acts as a feedback neuromodulator system. Clinically, the inhibition of
the glutamatergic transmission is thought to be responsible of locomotor effects, catalepsy,
hypothermia and analgesia, whereas the effect on GABA transmission could be involved in memory,
stress and strengthening mechanisms. Activation of CB1 receptors is known to modulate several
neurotransmitter systems including the dopamine system. The effects of cannabis are mediated by D9-THC partial agonist at the cannabinoid 1 receptor and cannabis-stimulated dopamine release is
thought to play a major role in the occurrence of psychomimetic symptoms. Since dopamine neurons
are devoid of CB1 receptors, their increased activity may be due to a change in the balance between
the GABA and glutamate afferences. In animal models, administration of THC or other cannabinoids
led to a dopamine release in several brain regions including the nucleus accumbens, the striatum and
the pre frontal cortex.
3.2. Hypotheses explaining the cannabis-psychosis association
There are 3 main possible explanations for the cannabis-psychosis association. Two are based on
causal associations: either cannabis causes psychosis or psychosis causes cannabis consumption. A
third explanation is the existence of a non-causal association because of the existence of a third
element associated (causally or not) with both psychosis and cannabis use.
3.2.1. Cannabis causes psychosis
Most authors, based on temporal sequence between onset of cannabis use and onset of psychoses, but
also on theoretical and pathophysiological arguments, suggested that cannabis is involved in the
development of psychosis. Almost all agree that adolescence may be a particular vulnerable period to
the effects of cannabis. During adolescence, the central nervous system undergoes several
developmental and maturational processes that can, in theory, be disrupted by cannabis exposure.
Several animal studies confirm this window of vulnerability hypothesis. THC may disrupt the
regulatory role of the endocannabinoid system on synaptic GABA and glutamate balance, responsible
of the dysregulation of the dopamine system, which underlie a large range of psychotic symptoms.
Indeed, THC appears to enhance mesolimbic dopaminergic activity and cannabinoid receptors appear
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to decrease the uptake of dopamine. Therefore, it has been suggested that cannabis use may contribute
to the development of psychotic symptoms by leading to a sensitization of the dopaminergic system.
Sensitisation in this case refers to a process by which intermittent cannabis exposure produces a
permanent change in dopaminergic responses. Thus, regular cannabis use may gradually render
individuals more sensitive to dopamine-induced perceptual and cognitive abnormalities.
Morphological and functional impairments in the hippocampus and prefrontal cortex have been
observed following chronic administration of synthetic cannabinoids in rat. The Quinn et al. study
[32] is of a particular interest because it shows that, following repeated THC exposure adolescent
rats display greater cognitive deficits than adult rats. The same study suggests that adolescent rats
are more vulnerable to developing addiction to cannabis as they seem to be less sensitive to the
aversive effects of the drug. Some of the studies in humans tend to support this hypothesis as they
suggest that early cannabis use confers greater risk of psychosis than later cannabis use.
However, other studies suggest that the key parameter is a greater cumulative exposure to cannabis
rather than an exposure during a sensitive period. Results of Stefanis et al. [33] showed that a 7 to 8
years delay is found between the age at initiation of cannabis use and age at onset of psychotic
illness, regardless of age at which cannabis use was initiated. Several smaller studies have found a
similar delay. In a previous meta-analysis of epidemiological studies that examined the relationship
between cannabis and psychosis, Moore et al. (2007) [1] reported that lifetime cannabis use
increases the risk of developing psychosis in a dose-dependent manner.
Whatever the mechanism by which cannabis is hypothesized to lead to psychosis, aetiological
theories must also account for the fact that only a minority of cannabis users develops psychosis.
This suggests that interaction with other environmental factors and/or genetic predisposition may
play a crucial role. To test this hypothesis, many gene-environment or environment-environment
interaction studies emerged, proposing 2 or 3-way interaction models to explain the relationship
between cannabis and psychosis. The best example of such models is the three-way interaction
between catechol-O-methyltransferase (COMT) polymorphism (val allele), cannabis use and
positive history of child abuse. In a sample of 918 individuals from a cross-sectional study, Vinkers
et al. [34] found that the Val-homozygous individuals were more likely to experience psychosis
after exposure to both cannabis use and childhood maltreatment than Met-heterozygous and Methomozygous individuals. In the same way, Alemany et al. [35] assessing psychotic experiences,
childhood abuse, cannabis use and COMT Val158Met genotypes in 533 individuals from the
general population, found that Val carriers exposed to childhood abuse are vulnerable to the
psychosis-inducing effects of cannabis. None of the two-way interactions tested (i.e. childhood
abuse-cannabis; childhood abuse-COMT or cannabis-COMT) were significant. These interaction
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studies strongly suggest that the association between childhood abuse, cannabis use and psychotic
experiences could be moderated by the COMT gene.
3.2.2. Psychosis induces cannabis consumption
Conversely, several researchers proposed that cannabis might alleviate some of the (negative)
symptoms present in early phases of the disease - the so-called self-medication hypothesis - and as
such that the association between cannabis and psychosis is due to psychosis leading to cannabis
consumption. However, the evidence for this hypothesis is, at present, weak. There are no clear
explanatory pathophysiological mechanisms and results were not replicated in prospective studies
with larger samples. Also, as mentioned, studies suggest that cannabis use generally precede the
onset of psychosis and that cannabis seems to worsen psychotic illness. For example, in a
prospective study of 245 individuals clinically at high-risk of psychosis, Dragt et al. [36] did not
support the self-medication hypothesis (i.e. use cannabis to alleviate first-psychotic symptoms) as
they demonstrated that the use of cannabis precedes the onset of psychosis. In the same way,
Arseneault et al. [37], in a longitudinal prospective study reported that cannabis use was associated
with an increased risk of schizophrenic symptoms, even after controlling for the existence of
psychotic symptoms at baseline (before onset of cannabis use).
Studies using self-report questionnaires to investigate reasons of cannabis consumption in individuals
with psychosis also failed to support the self-medication hypothesis as they found similar reasons for
cannabis consumption as in the general population, i.e, coping with unpleasant affect, enhancement of
their affect or socialization. Henquet et al. [38] found that cannabis use was not predicted by previous
changes in symptom level or mood, arguing also against direct self-medication effects.
3.2.3. The association between cannabis and psychosis is due to a third variable
As suggested earlier, the association between cannabis use and psychosis could be other than
causal. The two disorders could be the result of a common cause. At present there are no arguments
in favor of this hypothesis and the study by Veling et al [31] suggests that, at least the genetic
vulnerability is not common for the two disorders.
Also, the two conditions might be associated otherwise that through a common cause. Cannabis use
is often associated with other substance use disorders and these have been suggested by some
authors to be the cause for psychotic symptoms. The most problematic association is between
cannabis and tobacco, as most often cannabis is mixed with tobacco when smoked, thus making
difficult to disentangle the role of each substance. Furthermore, studies have shown that not only
tobacco is associated with risk for psychosis but also that, with reference to PLE, when adjusting for
tobacco consumption, the risk associated with cannabis is mitigated or disappears. In summary,
there is a well-documented hypothesis based on a toxicological approach and implies a toxic
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substance (THC) affecting the central nervous system (PFC, hippocampus, mesolimbic system)
during a critical period (adolescence), resulting in irreversible structural changes. The dose, the
exact time-window and duration of the exposure determine the severity and location of the
disturbance, leading ultimately to the development of psychosis.
However, some studies suggest that the association between cannabis and psychosis could be more
complex, and that maybe the different hypotheses may overlap. The study of Henquet et al. (2010)
[38] is of a particular interest because it showed that patients with psychosis were more sensitive
than healthy controls to acute mood-enhancing effects of cannabis on one hand, and to sub-acute
psychosis-inducing effects (of cannabis) on the other hand. The temporal dissociation between
acute rewarding effects and sub-acute toxic influences may be instrumental in explaining the
vicious circle of deleterious use in these patients. Thus, it may suggest that cannabis can be used to
alleviate dysphoric symptomatology in the early phase of use among psychotic patients (the selfmedication hypothesis), and secondly leads to impair psychotic symptomatology (the inducedpsychosis hypothesis).

4. Is schizophrenia preventable through cannabis cessation?


If we consider that cannabis is a risk factor for psychosis and especially for schizophrenia, then we
can assume that promoting cannabis cessation would have an impact on the incidence and evolution
of psychosis. Thus, subjects that are prevented from using cannabis would at best not develop
schizophrenia and if they do would have a later onset, a better prognosis or an attenuated form.
Cannabis as a preventable risk factor for schizophrenia has several advantages over the other risk
factors. Among them is the fact that it could be modified (unlike for example urbanicity at birth), it
is proximal to the onset of psychosis (unlike for example maternal influenza) thus more easy to
assess the effect of preventive measures, it is probably a risk factor and not merely a marker of
increased risk (as it is, for example, seasonality of birth), has biological relevance and, additionally,
is worth preventing for several other health related reasons.
However, in order to implement the prevention of cannabis use as a method of diminishing the
number of psychosis cases, there are two more conditions that should be taken into consideration:
the number of subjects needed to prevent (NNP) a case of psychosis has to be reasonable and
efficient methods to prevent cannabis use have to exist The prevention of schizophrenia through
cannabis prevention is an interesting debate. A lower NNP implies that early intervention among
cannabis users (i.e. before installation of a heavy use or an addictive disorder) has a significant
impact on the incidence of schizophrenia. Secondly, this would support the hypothesis that cannabis
is a risk factor for psychosis. Indeed, the NNP depends on the relative risk (RR) associated with
cannabis. But, for a more rigorous approach, we should take into account other parameters that
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influence NNP, like the incidence of the disorder to be prevented, i.e. psychosis or schizophrenia, in
the population and the prevalence of the risk factor, i.e. cannabis.
The figures for each of these variables (incidence of psychosis, prevalence of cannabis use and RR)
are somewhat uncertain and dependent of the context, thus making estimation of the NNP quite
different, based on the specific choices.
In the following paragraphs, we will try to make explicit the different possible choices and their
influence on the NNP results.
The RR to be considered is one that comes from studies in the same (or very similar) populations. It
is important to underscore that cannabis, as other risk factors (RF) for complex diseases, is a
component RF. That means that the risk associated with cannabis depends on the presence of other
RF and, as such, the RR associated with cannabis could change mightily from a population to
another, depending on the presence (prevalence) of the other component RF.
The incidence depends on the disorder considered (schizophrenia only or all of non-affective
psychoses) but the importance of this choice for the NNP is mitigated by the fact that the RR is less
important for non-affective psychosis. However, the incidence depends also on the period at risk
considered. This choice is, in turn, based on the theory about the transient or long-lasting effects of
cannabis on risk. In the extreme, using annual incidence will generate NNPs 10 to 20 times higher
than if lifetime incidence is considered (which could be a reasonable choice for the hypothesis of a
long lasting effect of cannabis - for example through permanent effect on the developing brain).
Incidence also depends on the population/subgroups of population considered: especially age
groups (e.g. usually a 3-fold variation between the 20-24 band and 40-45 age band) and the
presence of other risk factors that may have a great impact (e.g. family history is associated with a
10x increase in incidence).
The prevalence of cannabis consumption depends, obviously, on the definition of the risk factor e.g.
light of heavy use. Caution must be exercised to use the same definition as used for the RR calculation.
One important choice is which prevalence has to be linked to which incidence. Once more it
depends on theoretical considerations: if, for example, the effect is considered immediate and not
long-lasting the same age group seems appropriate if, on the other hand, a time lag between the
exposure to cannabis and the diagnosis of psychosis is supposed, the prevalence in a younger age
band has to be considered. This also could change the estimate of the prevalence (and thus of
NNPs) by a 2x factor.
A final consideration when approaching prevention is the efficacy of the preventive measures. If the
program to prevent cannabis consumption works only for 1 in 5 people the NNPs have to be
multiplied with 5.
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Some of these factors have already been mentioned by Hickman et al. [39], and the choices of
hypotheses leading to their calculation have been explicit. However, most often only their final
calculation and subsequent conclusion are cited.
An alternative calculation for NNP based on the hypothesis of a long term effect (15 years) and a
long lag between the use of cannabis and schizophrenia onset (5 to 10 years) will lead, using the
same RR to a NNP ten to twenty times smaller than the NNP calculated by Hickman et al. [39].
Thus, for example, in the most risk population (young males), the NNP will be of 125 to 250 (2500
in the above cited article). The reduction in NNP is related to the cumulative effects over a longer
period, and a lesser prevalence of cannabis use in subjects 16 to 19 compared to 20-24 years.
Even more optimistic NNP could be obtained if based on studies suggesting that early onset of cannabis
consumption is associated with an increased RR (e.g. 3 times higher in Arsenault et al. [37]).
As comparison, 118 patients with non-severe hypertension need to be treated for 5 years to prevent
one stroke, and it is well admitted that hypertension is an important risk factor for stroke. Our NNP
calculation provides then another approach to establish a link between cannabis use and
schizophrenia. Nevertheless, it remains unclear how the NNP would vary with cannabis use severity.
Indeed, with the example of stroke, when severe hypertension is considered, the NNP decreases to 29.
Finally, we do not want to suggest that our estimation is more realistic that the one made by
Hickman et al. As mentioned above, in this section we only tried to underscore the uncertainties that
are associated with NNPs calculations, most of them due to our lack of data on the cannabispsychosis relation. Depending on the answers that future research will bring, it is possible that,
provided that efficient prevention methods are developed, prevention of psychosis through
prevention of cannabis use might be not as hopeless as previously thought.

5. Summary and conclusion


Psychotic disorders are among the most severe psychiatric disorders and the presence of psychotic
symptoms in other disorders is often considered a marker of severity.
Based on clinical, pathophysiological and epidemiological data, cannabis consumption has been
considered a putative risk factor for psychotic disorders.
The study of psychosis in an acute and transient phase (e.g. cannabis induced psychotic disorder), or
in milder phenotypes (e.g. schizotypy, psychotic-like experiences), helps to better understand the
mechanisms underlying the association between cannabis and psychosis.
The fact that only a minority of cannabis users develop psychosis suggests that interaction with
other environmental factors (e.g. childhood abuse) and genetic factors (e.g. COMT) play an
essential role.
Adolescence seems to be the vulnerable period when cannabis may deregulate several
developmental and maturational processes, and a potential cumulative role of cannabis during this
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Challenges and Controversies

period is suggested. Mechanisms of action of exogenous cannabinoids on the endocannabinoid


system and neurotransmission remain unclear, and little is known about how these may contribute
to the formation of psychotic symptoms.
Unfortunately, only the model based on the toxic effect of THC is widely explored in the
literature and little is published on the role of other components of cannabis and on other
cannabis-psychosis hypotheses.
In addition, although cannabis use is an important risk factor in psychosis, it is only one among
many others, and other research directions have to be developed. But, contrary to almost all other
risk factors in psychosis, cannabis could be primary and/or secondary prevented, which could be
significant, considering the disability and the cost of psychosis.
It is known that drug cessation programs in schizophrenia are still not very efficient, with high
rates of relapse, but more optimistic results with early interventions in psychotic first-episodes or
in individuals at risk of psychosis could be expected. Better programs for prevention could
diminish the NNP.
Even if the real impact in the prevention of schizophrenia seems to be very modest, with a high
NNP, cannabis prevention, particularly in adolescence would have positive consequences on
physical and mental health, social interactions, schooling and road safety.

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