Medications between psychiatric and addictive disorders

Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 215–223

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Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp

Medications between psychiatric and addictive disorders Laurence Lalanne a,d,⁎, Pierre-Eric Lutz e,f, Benoit Trojak c, Jean-Philippe Lang d, Brigitte L. Kieffer a,f, Elisabeth Bacon b a

Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Molé-culaire et Cellulaire, INSERM U-964, CNRS UMR-7104, Université de Strasbourg, France Inserm U-1114, Department of Psychiatry, University of Strasbourg, France Department of Psychiatry and Addictology, University Hospital of Dijon, France, EA 4452, LPPM, University of Burgundy, France d CHRU de Strasbourg-INSERM1114, Department of Psychiatry, University of Strasbourg, France e McGill Group for Suicide Studies, Douglas Mental Health research Centre, McGill University, Montréal, Canada f Douglas Mental Health Research Centre, McGill University, Montréal, Canada b c

a r t i c l e

i n f o

Article history: Received 3 August 2015 Received in revised form 2 October 2015 Accepted 25 October 2015 Available online 27 October 2015 Keywords: Dual diagnosis Addiction Psychiatric disorders Depression Schizophrenia Cognition Mirtazapine Modafinil Clozapine

a b s t r a c t Introduction: Many epidemiological studies have revealed a frequent co-occurrence of psychiatric and substance use disorders. The term used in the literature to refer to this co-occurrence is dual diagnosis. The high prevalence of dual diagnosis has led physicians to observe the effects of medication prescribed to treat psychiatric disorders on the co-occurring substance use disorder and vice versa. The concept of medications between psychiatric and addictive disorders stems from these clinical observations, alongside which, however, it has developed from the observation that both psychiatric and substance use disorders share common neurobiological pathways and trigger common cognitive disorders. This has led researchers to develop medications on the basis of neurobiological and cognitive rationales. Material and method: In our article, we review peculiar medications based on neurobiological and cognitive rationales and that have an impact in both psychiatric and addictive disorders. Results: We highlight how interesting these new prescriptions are for clinical observation and for the treatment of patients suffering from dual diagnosis. Conclusion: We then go on to discuss the interest in them from the perspective of clinical practice and clinical research, in that the development of medications to treat dual diagnosis helps to further our knowledge of both psychiatric and substance use disorders. © 2015 Elsevier Inc. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Material and method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Medications between psychiatric and addictive disorders prescribed according to a neurobiological rationale . . . . . . . . . . . . . . 3.1.1. Antidepressant drugs effective for treating psychopathological symptoms of drug abstinence . . . . . . . . . . . . . . . . . . 3.1.2. Opioid substitution drugs effective for treating depression-like symptoms during protracted abstinence . . . . . . . . . . . . . 3.1.3. Might be antipsychotics a treatment for addictive disorders? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Medications between psychiatric and addictive disorders prescribed according to a cognitive rationale . . . . . . . . . . . . . . . . . 3.3. The synergistic contribution of clinical observations and neurobiological rationales of dual diagnoses to enriching the therapeutic arsenal for psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. General discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: INSERM1114 — Department of Psychiatry, University of Strasbourg, 1 Place de l'hôpital, 67000 Strasbourg, France. E-mail addresses: [email protected] (L. Lalanne), [email protected] (P.-E. Lutz), [email protected] (B. Trojak), [email protected] (J.-P. Lang), [email protected] (B.L. Kieffer), [email protected] (E. Bacon).

http://dx.doi.org/10.1016/j.pnpbp.2015.10.009 0278-5846/© 2015 Elsevier Inc. All rights reserved.

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Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Over the past few years, many epidemiological studies conducted into substance use disorders have shown a high level of co-morbidities between substance use and psychiatric disorders (Farrell et al., 2001; Grant et al., 2007; Husky et al., 2008; Habibisaravi et al., 2015; Ross and Peselow, 2012; Cottencin, 2009; Ohlmeier et al., 2007). As regards the two main substances used worldwide, namely alcohol and tobacco, studies found a strong comorbidity between drug dependence and mental disorder. In the 2001–2002 American National Epidemiological Survey on Alcohol and Related Conditions (NESARC-USA), the authors pinpointed the existence in the general population of associations between drug use and mood (odds ratio = 3.5, 99% CI = 2.7–4.5), and between alcohol use and anxiety disorders (odds ratio = 2.7, 99% CI = 2.1–3.7) (Grant et al., 2005; Compton et al., 2007). Furthermore, there is a higher risk of suicide in women who smoke more than 25 cigarettes per day (Husky et al., 2008; Tanskanen et al., 1998; Hemenway et al., 1993). Recently, Chen et al. showed in young adults not only that suicide was associated with smoking (OR = 3.69, 95% CI 1.85–7.39), but also that adolescents who were exposed to secondhand smoking showed an increased risk of suicide for N20 cigarettes per day (OR = 2.83, 95% CI 1.54–5.20), and already for 1–20 cigarettes per day (OR = 1.47, 95% CI 0.94–2.30) (Chen et al., 2015). People suffering from psychiatric disorders, on the other hand, show high levels of substance use disorders. For example, major depression has been observed to be associated with alcohol dependence (OR = 3.7, 95% CI = 3.1–4.4) (Grant et al., 2007) and, in women, with smoking (Husky et al., 2008). Moreover, Thoma and Daum reported that patients with schizophrenia have a lifetime prevalence of 50% of suffering from a comorbid substance use disorder, with cannabis, alcohol and tobacco the drugs most frequently used. According to Callaghan et al. (2013), the prevalence of smoking among individuals with psychiatric conditions is approximately 2 to 4 times higher than in the general population. The authors also observed that tobacco-related conditions appear to be responsible for approximately 53% of all deaths in schizophrenia cohorts, and 48% and 50% of all deaths in bipolar and depression cohorts respectively. In addition, it is well known that there is a link between anxiety disorders and substance use disorders (Callaghan et al., 2013). For example, Fatseas et al. showed that there is a strong correlation between PTSD and opiate addiction, with a lifetime prevalence of drug consumption of between 26% and 35% (Fatséas et al., 2010). Dual diagnosis is the term used to refer to the co-occurrence in the same patient of a substance use disorder and a psychiatric disorder (Błachut et al., 2013; Murthy and Chand, 2012). The nature of the preexisting trouble may be of importance, and it has been observed, for example, that phobia seems to precede addiction (Compton et al., 2000, 2007), whereas addiction seems to precede generalized anxiety (Callaly et al., 2001; Back and Brady, 2008). Studies report that most frequently it is the psychiatric disorder that seems to manifest itself before the substance use disorder, but regardless of the order, their co-occurrence is very frequent. Consequently, medication prescribed initially for psychiatric diseases could have an impact on substance use disorders and vice versa, and these potential effects can be clinically observed by the physician. For example, people who suffer from anxiety and substance use disorders are usually prescribed antidepressant drugs for their anxiety. This then gives the clinician an opportunity to observe the potential benefits of psychiatric medication like antidepressants for the substance use disorders of their anxious patients. Some psychiatric medication has already been shown to have certain benefits for treating substance use disorder. Some authors have since proposed

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specific medication that might be effective as treatment of both conditions, i.e. for dual diagnosis (Graves et al., 2012; Murthy and Chand, 2012; Schnell et al., 2014). The concept of “medications between psychiatric and addictive disorders” refers to the medication that has resulted from these observations. It is expected that special medication will be able to treat both psychiatric and substance use disorders. Such medication has been developed on the basis of not only clinical observations but also neurobiological and cognitive rationale. In drug addicts, there is some modification of neurotransmission, involving dopaminergic, serotoninergic, glutamatergic, opioid neurotransmission system, as well as GABAergic, and norepinerphrinergic systems, coupled with changes in neuroplasticity. Neurobiologists and physicians have also gained useful knowledge from observing drug abstinence. In the case of protracted abstinence, the dysregulation of dopamine and serotonin transmission is characterized by a drop in their secretion and may subtend many clinical symptoms commonly described during abstinence, such as irritability, tiredness, anhedonia, lack of motivation and dysphoria (Zorrilla et al., 2014). In mice, heroin protracted abstinence provokes a decrease in social interactions and depressive disorders (Goeldner et al., 2010). These symptoms could be associated with a serotoninergic system dysregulation via the kappa dynorphinergic system (Lalanne et al., 2014). Otherwise, these symptoms appear to be quite similar to the symptoms of depression, which are characterized by a decrease in serotonin, dopamine and norepinephrine secretion (Blier, 2013; Shao et al., 2014). These observations have led physicians to test certain anti-depressants as treatment for protracted abstinence. In addition, cognitive impairments are present in both drug abuse and psychiatric illnesses. More specifically, mnesic, temporal, attentional, and executive impairments are all observed with substance use disorders (Gould, 2010) as well as psychiatric disorders, particularly depression (Papakostas, 2014) and psychotic disorders (Vidailhet, 2013). These observations explain why some medication for cognitive disorders which was initially developed to treat neurological or neuropsychiatric disorders has since been adapted in psychiatry and tried in the field of addictology. Although these rationales help to assess the relevance of use of many medicines in the context of dual diagnosis, the use of such medications is often the result of clinical observations. 2. Material and method In our article, we describe some medications developed as a result of neurobiological and clinical observations, as well as some stemming from cognitive rationales that may help to assess whether or not the medication in question is relevant for use (see table 1). It is expected that these rationales can be used to develop clinical research and to improve treatment for addiction in the future. 3. Results 3.1. Medications between psychiatric and addictive disorders prescribed according to a neurobiological rationale 3.1.1. Antidepressant drugs effective for treating psychopathological symptoms of drug abstinence Many serotoninergic ligands have been used to treat addiction and especially depression-like disorders associated with protracted abstinence, given that addiction and depression could potentially benefit from the functional and structural interdependence that dopamine

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Table 1 Here are reported references about medications between psychiatric and addictive disorders according to three rationales: neurobiological, cognitive and clinical.

Treatments

Rationales

Psychiatric diseases

Addictive diseases

References

– Mirtazapine

Neurobiological

– Depression

– Psychostimulants

– Afshar et al., 2012

rationale

Cruickshank et al., 2008 Zueco Pérez, 2002 – Alcohol

– Liappas et al., 2004 and 2005 Yoon et al., 2006

– Methadone and Buprenorphine

– Opioid

– Dean et al., 2004; Dyer et al., 2001

Cognitive rationale – Modafinil

– Volonteers

– Cocaine

– Dackis et al., 2003b Malcolm et al., 2006

– Metamphetamine

– De la Garza et al., 2005; Kalechstein et al., 2010; Hester et al., 2010

– Working memory

– Cannabis

– Sugarman et al., 2011

– Alcohol

– Joos et al., 2013

– ADHD

– No addictive disease

– Turner et al., 2004a

– Schizophrenia

– No addictive disease

and Response inhibition – Global cognition

– Michalopoulou et al., 2015; Turner et al.,

set shifting

2004b – Cocaine – Methylphenidate

– Li et al., 2010; Levin et al., 2007

– ADHD – Metamphetamine

– Delavenne et al., 2013 – Konstenius et al., 2014

Clinical rationale – Atypical Anti–

– Schizophrenia and psychosis

– Opiates

– Zimmet et al.,

psychotics :

2000; Gerra et al.,

Olanzapine, quetiapine,

2006; Kern et al., 2014

Aripiprazole, ziprasidone

– Cocaine

Risperidone

– Longo, 2002; Sabioni et al., 2012 Anton et al., 2008; Brunetti et al., 2012; Stoops et al., 2007

– Cannabis – Clozapine superiority as

– Schnell et al., 2014

– Nicotine – Wijesundera et

compared to other

al., 2014; Wu et al., 2013

atypical anti–psychotics – Substance use disorders

– Zimmet et al., 2000; San et al., 2007; Wijesundera et al., 2014; Wu et al., 2013

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and serotonin systems have in common (Filip et al., 2006; Bubar and Cunningham 2006). Based on this reasoning, a number of serotoninergic and tricyclic anti-depressants were investigated in dual diagnosis, but their effectiveness in respect of addiction was poor, probably because of their weak potentiality to improve the dopamine imbalance during protracted abstinence (Zorrilla et al., 2014). Some atypical antidepressants such as mirtazapine could be more interesting in terms of their overall monoaminergic action, particular on the serotoninergic, norepinephrinergic and dopaminergic neurotransmission systems (Masana et al., 2012). In fact, mirtazapine, which shows a negligible affinity for the re-uptake transporters, indirectly increases monoamine transmission, presumably via antagonist activity on multiple receptors, including norepinephrine NEα2 and serotonin 5-HT2A, and results in higher levels of norepinephrine (especially in the prefrontal cortex) and serotonin (Anttila and Leinonen, 2001; de Boer et al., 1996; Hoyer, 1988; Kooyman et al., 1994 and Kelder et al., 1997). Otherwise, mirtazapine 5-HT2C antagonism (5-HT2C receptors located on cell bodies of dopaminergic neurons) increases the level of dopamine in the nucleus accumbens, prefrontal cortex and striatum, the main regions involved in substance use disorders (SUDs) (Bubar and Cunningham, 2006; Engleman et al., 2008). The Mirtazapine 5HT-3 antagonist action is related to an anti-addiction effect that remains poorly understood but that has been observed at preclinical (Davidson et al., 2002) and clinical (Johnson et al., 2000, 2013) levels, and especially in patients who have genetic polymorphisms of the HTR3A and HTR3B genes (which encode the 5-HT3 receptor subunits A and B), which predict a treatment response to ondansetron, a 5-HT3 antagonist (Johnson et al., 2013). Finally, the mirtazapine histaminergic H1-antagonist effect is associated with an anxiolytic effect. Consequently, by raising the levels of all cerebral monoamines, mirtazapine could be very interesting for treating the craving and dysphoria that occur during withdrawal and protracted abstinence, particularly in the case of psychostimulant addiction (Graves et al., 2012 for review; Cruickshank et al., 2008; Afshar et al., 2012; Zueco Pérez, 2002), and also in patients suffering from alcohol dependence (Liappas et al., 2004, 2005), especially in the case of comorbid depressive disorders (Yoon et al., 2006). Finally, Napier and Graves showed some efficacy of mirtazapine on depressive symptoms and at preclinical level in opioid withdrawal. This suggests a possible efficacy of mirtazapine in heroin withdrawal but until now, there has been no clinical trial to confirm this hypothesis (Napier and Graves, 2011). During metamphetamine withdrawal and abstinence, for example, mirtazapine has been shown to reduce symptoms such as anxiety, anhedonia, irritability, paranoid ideation and fatigue, and to increase how long patients sleep (McGregor et al., 2008). As regards heroin addiction, some clinical case descriptions have reported that mirtazapine use is associated with an attenuation of clinical withdrawal symptoms (Pollice et al., 2008). In summary, atypical antidepressants like mirtazapine might be very useful for helping to cope with withdrawal symptoms and protracted abstinence by restoring the balance of monoaminergic neurotransmission systems. 3.1.2. Opioid substitution drugs effective for treating depression-like symptoms during protracted abstinence Similarly, clinical observations, confirmed by neurobiological proofs, suggest that some pharmacological treatment for SUDs could have potentially beneficial effects on depressive symptoms. Methadone and buprenorphine have been shown to cause a decrease of dysphoria in patients suffering from heroin addiction. In fact, the idea of treating depression with opiates is not new. Until the 1950s, opiates were used to treat depression, but due to their addictive potentialities they were replaced by anti-depressant drugs (Tenore, 2008). Many studies have established a link between depression and dysregulation of the opiate system. Firstly, there is an increase of the mu opioid receptors (39%) in the prefrontal cortex of patients who commit suicide, suggesting that there is an upregulation of mu opioid receptors following a lack of endorphins (endogenous peptide agonist of the mu opioid receptor)

(Gross-Isseroff et al., 1990). Secondly, administering endorphins to patients suffering from depression seems to reduce their depressive symptoms after a delay of 4 h and causes all symptoms to disappear completely in half a day (Pickar et al., 1981). Activation of the opioid mu receptor leads to a lowering of depressive and anxiety behaviors by increasing dopamine transmission (Lutz and Kieffer, 2013) and reducing cortisol secretion (Judd et al., 1982). This is also the main anti-depressant mechanism of methadone and buprenorphine, as well as of opiate drugs. Buprenorphine is a partial kappa opioid receptor antagonist, which is associated with an anti-depressant effect (Lutz and Kieffer, 2013). Recent publications suggested that buprenorphine could be used at low dosage for its antidepressant effect in the treatment of resistant depression (Karp et al., 2014), an effect that was observed in studies at preclinical level (Falcon et al., 2015). Some other anti-depressant mechanisms are related to methadone action (Tenore, 2008). Methadone blocks the catecholamine recapture with a low affinity, in the same way that tricyclic anti-depressants do, and results in raised serotonin levels by blocking its transporters. Finally, like NMDA antagonists, methadone blocks NMDA receptors (Inturrisi, 2005), resulting in a lowering of glutamate effects and stimulation of serotonin secretion. These neurobiological effects have important clinical implications, and various studies have shown buprenorphine and methadone to have certain antidepressant effects in patients suffering from heroin addiction (Dean et al., 2004; Dyer et al., 2001). It has emerged from these studies that there is a correlation between methadone blood concentrations and its anti-depressant effects (Dean et al., 2004; Dyer et al., 2001). However, it should be borne in mind that although these treatments could help patients break the vicious cycle of addiction, methadone and buprenorphine are opiates of substitution and are not supposed to treat addiction. 3.1.3. Might be antipsychotics a treatment for addictive disorders? As a result of their pharmacological action, antipsychotic drugs can be expected to be capable of treating patients suffering from addiction, but the current state of knowledge leads to mixed conclusions. The positive reinforcements (pleasure associated with drugs and gambling) are mediated principally by dopamine and their action on dopamine receptors (Volkow et al., 2011; Zack and Poulos, 2009) which are expressed in the limbic striatum. Meanwhile, interestingly, it is known that dopamine receptors are blocked in this brain area by antipsychotic drugs (Lako et al., 2013). Consequently, antipsychotic drugs can be expected to be able to reduce or eradicate addictive behavior. However, although recent studies showed that increasing dopamine receptor DR3 blockade could be interesting for reducing addictive behavior in animal models (Le Foll et al., 2014), few of the antipsychotic drugs tested to date in humans and animals with addictive disorders owing to their pharmacological properties have proved interesting as potential treatments (Kishi et al., 2013). Moreover, the strong DR2 blockade induced by classic antipsychotics such as haloperidol could trigger increased craving (a strong blockage prevents dopamine rewarding effects in the limbic striatum, resulting in an increase in craving) in comparison with atypical antipsychotics which produce a weak blockade of DR2. For example, Dawe et al. (1995) showed that a single dose of haloperidol increases nicotine intake in smokers. Moreover, nicotine dependence is greater in patients treated with haloperidol (Kim et al., 2010). According to Dawe et al. (1995), this increase in nicotine intake could be a strategy used by smokers to compensate for the reduction in reward induced by Haldol DR2 antagonism in the striatum. It is generally recommended that patients suffering from the dual diagnosis, i.e. a psychiatric disorder coupled with an addictive disorder, particularly an addiction to opiates (Gerra et al., 2006; Kern et al., 2014; Zimmet et al., 2000), cocaine (Longo, 2002; Sabioni et al., 2012), and nicotine (Procyshyn et al., 2001; Wijesundera et al., 2014; Wu et al., 2013), should be prescribed atypical antipsychotics rather than classical antipsychotics. However the authors recommend a greater methodological

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strictness, including using a placebo group in the studies, so that health professionals can better determine the real effectiveness of antipsychotic medication for the treatment of substance use, especially in patients with schizophrenia (Brunetti et al., 2012; Sabioni et al., 2012). Some studies have suggested that risperidone has some positive effect in the case of cocaine (Akerele and Levin, 2007; De la Garza et al., 2005) and metamphetamine abuse, and aripiprazole in the case of alcohol and cocaine dependency (Anton et al., 2008; Brunetti et al., 2012; Stoops et al., 2007). Of all the antipsychotic drugs available, one, clozapine, seems to present a real interest for treating addictive disorders, but only in patients also suffering from mental illness, in other words as medication between psychiatric and addictive disorders. In case of nicotine addiction, studies have shown that clozapine enhances smoking reduction when compared with nonclozapine atypical antipsychotics in patients with schizophrenia (Kim et al., 2010; Wijesundera et al., 2014; Wu et al., 2013). Furthermore, it has been shown that, overall, substance dependency decreases significantly (by around 85%) when patients suffering from psychiatric and addictive disorders switch from classic antipsychotic drugs to clozapine (Zimmet et al., 2000; Procyshyn et al., 2001; San et al., 2007). This effect could be related to a clozapineinduced reduction in the euphoric effects and psychotic symptoms induced by addictive substances, such as the paranoid ideas triggered by cocaine use (Farren et al., 2000). Although the effect of clozapine is clinically well established, the mechanisms that render it superior to other antipsychotics for the treatment of double diagnosis are yet not fully understood. Unlike haloperidol, the chemical structure of clozapine facilitates a relatively rapid dissociation from DR2 receptors (Seeman, 2014), and clozapine has a higher affinity for DR3 and DR4 than other antipsychotics (McCormick et al., 2013), as well as being associated with a reduction in addictive behavior in murine (Le foll et al., 2014). Furthermore, preclinical studies suggest that dysregulations in dopaminergic activity may be linked to glutamatergic dysfunction in schizophrenia (Scoriels et al., 2015). In this way, recent works have shown that the antipsychotic action of clozapine could be related to the transcriptional down regulation of Arc, a gene involved in synaptic plasticity and in the regulation of AMPA glutamate receptor in medial cortical areas (Collins et al., 2014). As a consequence, clozapine action could be due to its impact on many systems, which are dysregulated in schizophrenia, and its lesser action on dopaminergic system, notably DR2 receptors in striatum, inducing an increase of craving. In patients without mental illness, however, there is no advantage to be gained from prescribing antipsychotic drugs rather than a placebo to treat cocaine or psychostimulant addiction or abstinence (Kishi et al., 2013, metanalysis). A systematic review of placebo randomized trials showed that antipsychotics did not improve the maintenance of abstinence, or failed to reduce drinking or craving in patients with alcohol dependency (Kishi et al., 2013, metanalysis). So far, there is nothing to support the use of antipsychotic medication to treat addictive disorders if patients are not also suffering from some other psychiatric disease, and, based on reports, this is particularly true in the case of cocaine addiction (Amato et al., 2007). Consequently, although a neurobiological rationale exists for prescribing antipsychotics in patients with substance use disorders, randomized controlled trials failed to demonstrate that this medication had a positive effect on addictive behavior. In fact, it is only clinical observations which tend to recommend prescribing atypical antipsychotics rather than classic antipsychotics in cases of double diagnosis, in order to prevent the heightened craving induced by classic antipsychotics. 3.2. Medications between psychiatric and addictive disorders prescribed according to a cognitive rationale As neuropsychological and clinical observations have shown, patients suffering from substance use disorders develop cognitive impairments such as executive, mnesic, attentional and temporal disorders (Gould, 2010) also found in other pathologies such as neurological,

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neuropsychiatric and psychiatric disorders. Based on these observations, clinicians tried to treat patients suffering from types of addictive behavior with medication intended to improve cognitive deficits previously prescribed in neurological and psychiatric disorders (Sofuoglu et al., 2013). In his article, Sofuoglu et al. (2013) proposes to test drugs that enhance cognition in patients suffering from addiction, particularly during protracted abstinence. According to him, such medication could help patients continue with their abstinence or help them cut down on their addictive behavior. Clinical trials have shown that methylphenidate, which is used to raise attention levels in patients suffering from Attention Deficit Hyperactivity Disorder (ADHD), has a tendency to enhance the executive performance, and especially response inhibition (Li et al., 2010; Levin et al., 2007) of patients addicted to psychostimulants by reducing their craving for cocaine (Levin et al., 2007). Delavenne et al. (2013) showed recently that methylphenidate may be effective in treating ADHD symptoms in substance use disorder, thus preventing cocaine-induced psychosis (Delavenne et al., 2013). Another recent study in criminal offenders showed a decrease of attention deficit hyperactivity disorder symptoms and a decrease of the risk of relapse to substance use (Konstenius et al., 2014). Finally, ADHD is a frequent comorbidity in SUD patients. Pérez de los Cobos recommended that clinical decisions should be individualized and based on a careful analysis of the advantages and disadvantages of pharmacological treatment for ADHD on a case-by-case basis in the context of active substance use disorder (Pérez de los Cobos et al., 2014). So, methylphenidate might help to treat their psychostimulant addiction. Moreover, patients with ADHD frequently present a psychostimulant addiction to amphetamine or cocaine. Since they suffer from attentional impairments and present difficulties focusing on a task, their drug consumption might be regarded as an attempt to increase their cognitive abilities. Prescribing methylphenidate for ADHD patients suffering from drug addiction could have a positive impact on their cognitive disorders which are due to both psychiatric and addictive disorders, given that one can observe a combination of cognitive symptoms induced by ADHD and those induced by addictions, a pattern which is ample justification for prescribing methylphenidate, the classic treatment for ADHD. Clinicians do not commonly accept the prescription of a psychostimulant such as methylphenidate to enhance cognitive abilities in patients suffering from double diagnosis, and there is no consensus about whether it could help patients suffering only from addiction to maintain their abstinence. Otherwise, other types of medication regarded as cognitive enhancers, such as modafinil, have been tested on addictive behavior (Sofuoglu et al., 2008). Modafinil, which is not currently considered a psychostimulant, is an agonist of the dopamine receptors DR1 and DR2, and of the norepinephrinergic α receptors, and is known to inhibit serotonin, dopamine, and norepinephrine transporters, to act on the orexinergic system and to activate glutamatergic release. It has been shown to improve cognitive performance in sleepdeprived volunteers (Muller et al., 2004), ADHD patients (Turner et al., 2004a) and schizophrenia patients (Ballon and Feifel, 2006; Michalopoulou et al., 2015;Turner et al., 2004b). Numerous studies have shown that modafinil could help patients suffering from addiction-related cognitive impairments, such as those induced by cocaine, metamphetamine, alcohol and cannabis use (Dackis et al., 2003b; De la Garza et al., 2010; Hester et al., 2010; Kalechstein et al., 2010; Malcolm et al., 2006; Sofuoglu et al., 2008, 2013; Sugarman et al., 2011; Joos et al., 2013), and it also helps them to maintain their abstinence. These observations are even more interesting when due account is taken of the fact that 50% of schizophrenia patients suffer from an addiction throughout their life (Thoma and Daum, 2013), the drugs most commonly used being nicotine, cannabis and alcohol. Subsequently, patients who present the double diagnosis could specifically benefit from using modafinil to treat their cognitive impairments induced by both addictive and psychiatric disorders.

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3.3. The synergistic contribution of clinical observations and neurobiological rationales of dual diagnoses to enriching the therapeutic arsenal for psychiatric disorders Although these new treatments for double diagnosis seem mostly to be based on neurobiological and cognitive rationale, there are substantial clinical observations confirming their effects on humans, and a high degree of consistency is regularly found between neurobiological bases and clinical observations. Nonetheless, unusual treatments are still tested on patients in respect of whom all classic medication has proved ineffective. Such is the case, in particular, of naltrexone, an anti-addiction treatment that has been tested on patients suffering from autism (Wynn and Brunetti, 2009; Rossignol, 2009; Doyle and McDougle, 2012; Roy et al., 2015 a review). The idea of using this molecule stemmed from a neurobiological hypothesis, given that a number of studies have shown that the rates of opioid peptides are higher in the cerebrospinal fluid of patients with autism (Gillberg et al., 1985). Although this neurobiological rationale was controversial, some researchers (Panksepp, 1979; Panksepp and Sahley, 1987) subsequently suggested that opioid activity contributes to the neurochemical genesis of autism. In 1997, Sher proposed that autism is due to an overload of opioid peptides in the cerebrospinal fluid and, indeed, in the brain (Sher, 1997). Although there was strong criticism of this theory, some clinicians decided to test naltrexone on patients with autism. They observed that low doses of naltrexone (0.5 mg/kg) had a positive clinical effect on hyperactivity, tantrums, social isolation, stereotypical behaviors, self-mutilation, and irritability in children (Wynn and Brunetti, 2009; Rossignol, 2009; Doyle and McDougle, 2012; Roy et al., 2015 a review). Subsequently, following these clinical observations, naltrexone was regarded as having potential for treating autism, and it is currently a serious future candidate for treating the aforementioned symptoms in patients with autism. At present, there are other neurobiological hypotheses that are proposed as explanations for the effects of naltrexone in autism (Good, 2006). 4. General discussion Dual diagnoses are very frequent, and studying them makes it possible to observe the potential effects of psychiatric medication on addictive disorders and vice versa. After research aimed at identifying molecules with potential as medication for dual diagnoses was initially grounded in the neurobiological bases of addiction and psychopathology, it would ultimately appear now that it is clinical observations that hold the key for identifying and selecting effective medication for dual diagnosis and, a fortiori, for psychiatric disorders or addictive disorders. Furthermore, it gives the opportunity to associate medications which could improve both psychiatric and addictive diseases, for example in a patient suffering from depression and opiate addiction, a combination of methadone and mirtazapine. Many reviews reported that, in contrast to the effect of atypical antidepressants such as mirtazapine, selective serotonin reuptake inhibitors have a large interindividual variability in response to SSRIs (selective serotonin reuptake inhibitors) in alcohol dependence (Naranjo and Knoke, 2001, a review), in psychostimulant addiction (Zorick et al., 2011, a review), and in nicotine addiction (Covey et al., 2002, a review). Moreover, fluoxetine seems to have a higher effect as compared to sertraline. As a consequence, in spite of the fact that symptoms of dysphoria induced by addictive disorders could express themselves as depressive disorders, addictive and psychiatric disorders seem to be two distinct entities that behave really differently in their neurobiological mechanisms. As a consequence, it is likely that only some, but specific, medications could be transferred from one to the other field with a high efficiency. Clinical observations are what drive the prescription of existing treatments for other indications, resulting in new labels for existing medication. In the meantime, the development of medication specifically for dual diagnosis will help foster a

better understanding of the neurobiological mechanisms of addiction and psychiatric disorders, by highlighting those mechanisms that are common to both and those which are specific. It also provides an opportunity to highlight new pharmacological properties of the drugs, and to pave the way for developing new pharmacotherapies for not only double diagnosis but also addictive and psychiatric disorders separately. Within this way, we should identify in the future clinical situations, and cognitive disorders, in which the combination of treatments in dual diagnosis could be interesting. To improve our understanding of the medications' impact on the two diseases, we have to promote the improvement of care for addictive disorders of psychiatric patients, for example patients with schizophrenia, who show more severe depressive and anxiety comorbidities, as well as severe cognitive disorders, and who receive limited care for their addictive disorders (Kern et al., 2014; Lang et al., 2014). 5. Conclusion All in all, while double diagnoses are complex and difficult to treat owing to the combination of a range of different symptoms, including addictive, psychiatric, cognitive and somatic impairments, they can contribute towards a new clinical and neurobiological understanding of the diseases, and may constitute a boon for the development of new treatments and new treatment combinations. Promoting such new prescriptions in severe psychiatric disorders could help to better understand the impact of such medications. Contributors All named authors must have made an active contribution to the conception of the paper and ALL have critically reviewed its content and approved the final version submitted for publication. Laurence Lalanne, Elisabeth Bacon and Brigitte Kieffer decided the subject matter and perspective of the paper. Elisabeth Bacon, Laurence Lalanne and Benoit Trojak compiled the collection of reviews. Pierre-Eric Lutz and Jean-Philippe Lang contributed critical comments that improve the quality and originality of the resulting article. The latest version of the paper has been reviewed and approved by all the authors. Competing interests We know of no conflict of interest pertaining to the manuscript, whether financial, consultant, institutional or other, nor of any other relationships that might result in any bias or conflict of interest. We have no financial disclosure to make. We received no funding from any pharmaceutical company or industry. Acknowledgments Acknowledgments go to all of the authors for their respective contributions. References Afshar, M., Knapp, C.M., Sarid-Segal, O., Devine, E., Colaneri, L.S., Tozier, L., Waters, M.E., Putnam, M.A., Ciraulo, D.A., 2012. The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression. Am. J. Drug Alcohol Abuse 38 (2), 181–186. http://dx.doi.org/10.3109/00952990.2011.644002 (Epub 2012 Jan 5. PMID:22221171). Akerele E, Levin FR (2007) Comparison of olanzapine to risperidone in substance-abusing individuals with schizophrenia. Am. J. Addict. 16(4):260–268.PMID:17661193 Amato L, Minozzi S, Pani PP, Davoli M (2007) Antipsychotic medications for cocaine dependence. Cochrane Database Syst. Rev. 3:CD006306. doi/http://dx.doi.org/10.1002/ 14651858.CD006306. (PMID:17636840) Anton, R.F., Kranzler, H., Breder, C., Marcus, R.N., Carson, W.H., Han, J., 2008. A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence. J. Clin. Psychopharmacol. 28, 5–12. http://dx.doi.org/10.1097/jcp.0b013e3181602fd4 (PMID:18204334).

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