Keywords

comorbidity, dual diagnosis, dual disorders, mental disorders, psychiatric disorder, substance use disorders

 

Authors

  1. Balhara, Yatan Pal Singh MD, DNB (Psychiatry), MNAMS
  2. Kuppili, Pooja Patnaik MD (Psychiatry)
  3. Gupta, Rishab MD (Psychiatry)

Abstract

Background: "Dual disorder" or "dual diagnosis" refers to the co-occurrence of substance use disorder and psychiatric disorders. Prospective studies have shown that treatment outcomes, such as symptom levels, hospitalization rates, housing stability, and functional status, are worse among the patients with dual disorders as compared with those who have either of these disorders.

 

Objectives: The current article is aimed at reviewing the current state of evidence on neurobiology of dual disorders. Given the high prevalence of co-occurrence of substance use disorder and psychiatric disorders, it is important to explore the various facets of this association. The current review assimilates the information on neurobiological research on dual disorders and helps the readers gain insights into the current understanding on this theme.

 

Methods: The electronic database of PubMed was searched for relevant publications.

 

Results: The studies included in the review belonged to various domains of neurobiology including neuropathology, structural neuroimaging, functional neuroimaging, genetics, neurochemicals/neuroreceptors, and neuroendocrinology. Forty studies were included in the review.

 

Conclusions: Most of the issues related to the neurobiology of dual disorders remain inadequately studied. However, the current evidence suggests that the individuals with co-occurring disorders are likely to differ from those with either substance use disorders or psychiatric disorders alone on various neurobiological aspects. Hence, it is imperative to systematically study the various neurobiological aspects of dual disorders in the future.

 

Article Content

INTRODUCTION

"Dual disorder" or "dual diagnosis" refers to the co-occurrence of substance use disorder and mental disorders (Wittchen, 1996). The relationship between the two is complex. A large proportion of individuals with mental illness also experience substance-use-related problems. Similarly, individuals with disorders related to psychoactive substance use are at an increased risk of experiencing mental illness. Studies have suggested that nearly one third of people with all mental illnesses and approximately half of people with severe mental illnesses (including bipolar disorder and schizophrenia) also experience substance abuse. Conversely, more than one third of all alcohol abusers and more than half of all drug abusers also experience mental illnesses. The rate of co-occurrence of psychiatric disorders and substance use disorders is high even among those seeking treatment (Singh & Balhara, 2016). Despite the high prevalence of co-occurrence of psychiatric disorders and substance use disorders, there is proportionately limited research on dual disorders.

 

Prospective studies have shown that treatment outcomes, such as symptom levels, hospitalization rates, housing stability, and functional status, are worse among the patients with dual disorders as compared with those who have either of these disorders (Linszen, Dingemans, & Lenior, 1994; Swofford, Kasckow, Scheller-Gilkey, & Inderbitzin, 1996). Hence, it is imperative to study the various facets of dual disorders systematically. The current article is aimed at reviewing the current state of evidence on neurobiology of dual disorders.

 

METHODOLOGY

Search Strategy

The electronic database of PubMed was searched for relevant publications. The search was carried out in July 2016 and included publications indexed in PubMed July 2016. Boolean search was carried out using combinations of "neurobiology" and "diagnosis, dual (psychiatry)"; "functional neuroimaging" and "diagnosis, dual (psychiatry)"; "neurotransmitter agents" and "diagnosis, dual (psychiatry)"; "genetics" and "diagnosis, dual (psychiatry)"; "receptors, neurotransmitter" and "diagnosis, dual (psychiatry)"; "brain" and "diagnosis, dual (psychiatry)"; "electrophysiology" and "diagnosis, dual (psychiatry)"; and "neuroendocrinology" and "diagnosis, dual (psychiatry)." In addition, search was carried out using the MeSH term "diagnosis, dual (psychiatry)" alone. An additional published material was identified from the bibliography of the studies screened and evaluated. The study included literature published in peer-reviewed journals. Authors were not contacted for unpublished materials.

 

Study Selection

For the purpose of the present review, English-language peer-reviewed studies conducted among human subjects were included. Previous reviews were excluded from the present review. In addition, animal studies were also excluded from the present review.

 

Data Extraction

Information was extracted using a structured proforma from the studies that met the abovementioned inclusion and exclusion criteria. Data were extracted pertaining to the various subdomains of neurobiology, namely, neuropathology, structural neuroimaging, functional neuroimaging, genetics, neurotransmitters and neurotransmitter receptors, electrophysiology, and neuroendocrinology, The information was extracted by two authors using predefined criteria.

 

RESULTS

Study Selection and Characteristics

The search results and study selection have been presented in Figures 1 and 2.

  
Figure 1 - Click to enlarge in new windowFigure 1. Search algorithm and study selection.
 
Figure 2 - Click to enlarge in new windowFigure 2. Search results using various search terms.

Fifty-five relevant manuscripts were found after search using the search term "diagnosis, dual (psychiatry)." Forty of these studies were finally included in the current review. Fifteen studies were excluded for reasons specified in Figure 1. Boolean search combining different neurobiology-related terms with "diagnosis, dual (psychiatry)" resulted in 52 relevant studies. Thirty-one of these studies were included in the current review. The others were excluded because of reasons specified in Figure 2. The studies included in the current review have been listed in Table 1.

  
Table 1 - Click to enlarge in new windowTABLE 1

The studies included in the review belonged to the following domains of neurobiology: neuropathology (Hercher et al., 2009; Miguel-Hidalgo et al., 2002, 2006), structural neuroimaging (De Bellis et al., 2005; Mathalon et al., 2003; Sameti et al., 2011; Scheller-Gilkey et al., 1999; Schiffer et al., 2010; Sullivan et al., 2003; Woodward et al., 2006), functional neuroimaging (Bourque et al., 2013; Cornelius et al., 2010; Joyal et al., 2007; Mancini-Marie et al., 2006; Potvin et al., 2007; Thompson et al., 2013), genetics (Cheah et al., 2014; Gokturk et al., 2008; Huang et al., 2008; Johann et al., 2003; Lee et al., 2010; Nellissery et al., 2003; Onwuameze et al., 2013; Pierucci-Lagha et al., 2004; Verhagen et al., 2009; Yang et al., 2012, 2014; Zai et al., 2014; Zammit et al., 2007), neurochemicals/neuroreceptors (Araos et al., 2015; Gerra et al., 1994, 1997, 1998; Miller et al., 1986; Pavon et al., 2013; Potvin et al., 2008; Szobot et al., 2008; Thompson et al., 2012), and neuroendocrinology (Gerra et al., 2000; Karlovic et al., 2004).

 

Table 2 summarizes the salient features and findings of these studies.

  
Table 2 - Click to enlarge in new windowTABLE 2

DISCUSSION

The salient features of these studies on neurobiology of dual disorders included in the current review have been discussed below.

 

Substances Studied

Alcohol

All the published studies on neuropathology (Hercher et al., 2009; Miguel-Hidalgo et al., 2002, 2006) and structural neuroimaging (De Bellis et al., 2005; Mathalon et al., 2003; Sameti et al., 2011; Sullivan et al., 2003; Woodward et al., 2006) of comorbid disorders have been conducted among subjects with alcohol use disorders. Most of the studies on genetics have been conducted among subjects with alcohol use disorders (Cheah et al., 2014; Gokturk et al., 2008; Huang et al., 2008; Johann et al., 2003; Lee et al., 2010; Nellissery et al., 2003; Pierucci-Lagha et al., 2004; Verhagen et al., 2009; Zai et al., 2014).

 

Two studies that assessed the biomarkers/biochemical/neuroreceptors among individuals with disorders have been conducted among subjects with alcohol use disorders (Miller et al., 1986; Thompson et al., 2012). One study on neuroendocrinological aspects of dual disorders included subjects with alcohol use disorders (Karlovic et al., 2004).

 

Opioids

One of the studies on genetics has been conducted among subjects with opioid use disorders (Yang et al., 2012). Three of the studies that assessed the biomarkers/biochemical/neuroreceptors among individuals with disorders have been conducted among subjects with opioid use disorders (Gerra et al., 1994, 1997, 1998). One study on neuroendocrinological aspects of dual disorders (Gerra et al., 2000) and one study on genetics (Yang et al., 2014) included subjects with opioid use disorders.

 

Cannabis

One of the studies on genetics has been conducted among subjects with cannabis use disorders (Onwuameze et al., 2013). Two functional neuroimaging studies (Bourque et al., 2013; Cornelius et al., 2010) focused on cannabis use disorders.

 

Cocaine

Two studies assessed the biomarkers/biochemical/neuroreceptors among individuals with cocaine use disorders (Araos et al., 2015; Pavon et al., 2013).

 

Multiple Substances

One of the studies on genetics has been conducted among subjects with tobacco and/or cannabis use disorders (Zammit et al., 2007). Two structural neuroimaging studies included subjects with two or more different substance use disorders (Scheller-Gilkey et al., 1999; Schiffer et al., 2010). Except for the two functional neuroimaging studies (Bourque et al., 2013; Cornelius et al., 2010) that focused on cannabis use disorders, the rest included subjects with two or more different substance use disorders (Joyal et al., 2007; Mancini-Marie et al., 2006; Potvin et al., 2007; Thompson et al., 2013). Two studies that assessed the biomarkers/biochemical/neuroreceptors among individuals with disorders have been conducted among subjects with more than one substance use disorders (Potvin et al., 2008; Szobot et al., 2008).

 

Psychiatric Disorders Studied

Two of the three studies on neuropathology of dual disorders were conducted among subjects with suicidal behavior (Hercher et al., 2009; Miguel-Hidalgo et al., 2006). The third study was conducted among subjects with depressive disorder (Miguel-Hidalgo et al., 2002). Most of the studies on structural neuropathology of dual disorders have been conducted among subjects with schizophrenia (Mathalon et al., 2003; Scheller-Gilkey et al., 1999; Schiffer et al., 2010; Sullivan et al., 2003). Two studies included subjects with multiple psychiatric disorders (De Bellis et al., 2005; Sameti et al., 2011), and one was conducted among subjects with posttraumatic stress disorder (PTSD; Woodward et al., 2006). Except one study that assessed subjects exposed to a threat paradigm (Cornelius et al., 2010), the rest of the studies on functional neuroimaging of dual disorders were conducted among subjects with schizophrenia (Bourque et al., 2013; Joyal et al., 2007; Mancini-Marie et al., 2006; Potvin et al., 2007; Thompson et al., 2013). Studies exploring genetics of dual disorders have included subjects with attention deficit hyperactivity disorder (ADHD; Johann et al., 2003); antisocial personality disorder (ASPD; Yang et al., 2012); borderline personality disorder (BPD; Yang et al., 2014); depressive disorder (Nellissery et al., 2003; Pierucci-Lagha et al., 2004); depressive disorder and anxiety disorder (Lee et al., 2010); depressive disorder, dysthymia, and generalized anxiety disorder (Verhagen et al., 2009); multiple psychiatric disorders (Gokturk et al., 2008; Huang et al., 2008); and schizophrenia (Cheah et al., 2014; Onwuameze et al., 2013; Zai et al., 2014). Studies exploring neurochemical aspects of comorbid disorders have been conducted among subjects with ADHD (Szobot et al., 2008), anxiety disorders (Gerra et al., 1998), depressive disorders (Gerra et al., 1997; Miller et al., 1986), schizophrenia (Potvin et al., 2008), siblings with personality disorders (Gerra et al., 1994), suicidal behavior (Thompson et al., 2012), and multiple psychiatric disorders (Araos et al., 2015; Pavon et al., 2013). Studies exploring neuroendocrinological aspects have been conducted among subjects with depressive disorder (Gerra et al., 2000) and PTSD (Karlovic et al., 2004).

 

Types of Studies

Whereas most of the studies on neurobiology of dual disorders were observational (Araos et al., 2015; Bourque et al., 2013; Cheah et al., 2014; Cornelius et al., 2010; De Bellis et al., 2005; Gokturk et al., 2008; Hercher et al., 2009; Huang et al., 2008; Johann et al., 2003; Joyal et al., 2007; Karlovic et al., 2004; Lee et al., 2010; Mancini-Marie et al., 2006; Mathalon et al., 2003; Miguel-Hidalgo et al., 2002, 2006; Miller et al., 1986; Nellissery et al., 2003; Onwuameze et al., 2013; Pavon et al., 2013; Potvin et al., 2007; Sameti et al., 2011; Scheller-Gilkey et al., 1999; Schiffer et al., 2010; Sullivan et al., 2003; Swofford et al., 1996; Szobot et al., 2008; Thompson et al., 2012; Verhagen et al., 2009; Woodward et al., 2006; Yang et al., 2012, 2014; Zai et al., 2014; Zammit et al., 2007), a few were experimental (Gerra et al., 1994, 1997, 1998, 2000; Pierucci-Lagha et al., 2004; Potvin et al., 2008; Thompson et al., 2013). Most of the observational studies used a case-control design. One double-blind placebo-controlled trial assessed the effect of rapid tryptophan depletion on mood and urge to drink among patients with alcohol dependence and major depressive disorder (Pierucci-Lagha et al., 2004). The other interventional studies assessed neuroendocrinological responses to biochemical challenges among subjects with opioid dependence with comorbid anxiety disorder (Gerra et al., 1998), depressive disorder (Gerra et al., 1997), and depressive disorder and personality disorder (Gerra et al., 1994) and functional neuroimaging among subjects with comorbid substance use disorder and schizophrenia (Thompson et al., 2013).

 

Gender and Age Groups Studied

Most of the studies have been conducted among adult men with the exception of 15 studies that have also included female subjects (Cornelius et al., 2010; Gerra et al., 1997; Gokturk et al., 2008; Mancini-Marie et al., 2006; Miguel-Hidalgo et al., 2002, 2006; Onwuameze et al., 2013; Pavon et al., 2013; Pierucci-Lagha et al., 2004; Potvin et al., 2007, 2008; Sameti et al., 2011; Scheller-Gilkey et al., 1999; Thompson et al., 2013; Verhagen et al., 2009) and adolescents (De Bellis et al., 2005; Gokturk et al., 2008; Szobot et al., 2008). Three studies exclusively included female subjects (Gerra et al., 1997; Gokturk et al., 2008; Yang et al., 2014). In addition, some studies have included relatives of the individuals with dual disorders or substance use disorders (Gerra et al., 1994, 1997).

 

Existing Evidence on Neurobiology of Dual Disorders

The existing literature on neurobiology of dual disorders has explored only a few aspects related to this association.

 

Studies on neuropathology

Postmortem neuropathology studies suggest that, among individuals with alcohol dependence who die of suicide, the structural pathology in the cerebral cortex is related mainly to alcohol use status (Hercher et al., 2009; Miguel-Hidalgo et al., 2002, 2006). Whereas comorbid depressive disorder exacerbates some of this pathology, completed suicide is not associated with any additional changes in brain morphology in these regions.

 

Studies on structural neuroimaging

All the structural imaging studies have used magnetic resonance imaging (MRI) as a tool of investigation. Comorbidity of alcohol use disorder and schizophrenia worsens the adverse effect of either of the two conditions on certain regions of the brain (overall gray volume of the cerebral cortex, prefrontal gray matter volume; Mathalon et al., 2003) and regions not affected directly by schizophrenia (pontine structures; Sullivan et al., 2003). Among individuals with comorbid alcohol dependence and psychiatric disorders, a smaller prefrontal cortex is associated with early-onset drinking (De Bellis et al., 2005). In addition, it is likely that comorbid psychiatric disorder among those with alcohol dependence interferes with the recovery in brain volume deficit in subcortical regions observed after long-term abstinence from alcohol among individuals with alcohol dependence alone. Individuals with comorbid alcohol dependence and PTSD have a relatively smaller hippocampus volume, which could explain the increased risk of PTSD among those with alcohol dependence (Woodward et al., 2006). Comorbidity of schizophrenia and substance use disorders worsens the adverse effects associated with substance use in certain regions of the brain not affected directly by schizophrenia (anterior cingulate, frontopolar and superior parietal regions). The additive deficits associated with comorbid substance use disorder and schizophrenia are noticeable in nonplanning impulsivity as opposed to functional executive deficits that remain largely unaffected by the comorbidity (Schiffer et al., 2010).

 

The studies have implicated diverse regions of the brain among those with dual disorders. Overall gray matter volume of the cerebral cortex, prefrontal gray matter volume, pontine structures, and hippocampus are some of the brain regions that have been the focus of interest in these studies. More importantly, most of the findings from individual studies remain unreplicated. Hence, it is difficult to draw conclusive inferences based on the existing evidence.

 

Studies on functional neuroimaging

Most of the functional neuroimaging studies have employed functional MRI as a tool of investigation. Other functional neuroimaging tools used in these studies are blood-oxygen-level-dependent functional MRI and [11C]raclopride positron emission tomography. Among individuals with comorbid cannabis use disorder and schizophrenia, emotional memory and prefrontal lobe functioning are relatively better preserved as compared with those with schizophrenia alone (Bourque et al., 2013). Among individuals with comorbid schizophrenia and substance (heterogeneous) use disorders, the functioning of the medial prefrontal cortex and socioemotional processing are relatively better preserved (Thompson et al., 2013). In addition, there is a transient amphetamine-induced positive symptom change accompanied by a blunted dopamine release in these individuals. The frontal basal cortices are significantly less activated in individuals with comorbidity (schizophrenia, substance use disorders, and ASPD) during the assessment of measures of impulse control as compared with individuals with schizophrenia only and healthy controls (Joyal et al., 2007). However, higher activations are observed in frontal motor, premotor, and anterior cingulate regions in individuals with comorbidity. The findings suggested that emotional memory and prefrontal lobe functioning are relatively better preserved in individuals with comorbid schizophrenia and cannabis abuse relative to non-cannabis-abusing individuals with schizophrenia. A decrease in cannabis use among individuals with comorbid cannabis dependence and depressive disorder after fluoxetine administration is associated with an increase in amygdala reactivity among individuals who show a decrease in cannabis use after the treatment trial (Cornelius et al., 2010). Although the recognition of positive and negative emotions is impaired in non-cannabis-abusing subjects with schizophrenia relative to healthy controls, there is little difference between those with comorbid schizophrenia and cannabis abuse and healthy controls. Moreover, different regions of the brain get activated in response to such stimuli among individuals with comorbidity as compared with those with schizophrenia alone. Striatal dopamine release in response to amphetamine challenge is impaired among subjects with comorbid schizophrenia and substance dependence (Thompson et al., 2013).

 

Studies on genetics

Among the individuals with comorbid alcohol use disorder and depressive disorder, the frequency of the short allele at the SLC6A4 locus of serotonin (5-HT) transporter-linked polymorphic region is similar to those with depressive disorder alone (Nellissery et al., 2003). In addition, serotonergic neurotransmission has been found to have a role in modulating mood and alcohol urges among these individuals. The effect of the 5-HT transporter-linked polymorphic region polymorphism on major depressive disorder among those with alcohol use disorders is codependent on the presence of comorbid disorders and gender. Different variants of monoamine oxidase A (MAOA)-uVNTR polymorphisms modify the protective effects of the ALDH2*2 allele on individuals with comorbid alcohol use disorder and anxiety and depressive disorders in Han Chinese (Gokturk et al., 2008). Among women with comorbid alcohol use disorder and psychiatric disorder, there is a significantly higher frequency of the LL 5-HTT genotype. Moreover, contrary to findings among men, among women with alcohol use disorder, aggressive antisocial behavior is significantly linked to the presence of the high-activity MAOA allele. Among individuals with comorbid alcohol use disorder and ADHD, functional, relevant serotonin transporter gene promoter and the 5-HT2c receptor Cys23Ser polymorphism do not seem to contribute to the common genetic predisposition of alcohol dependence and ADHD (Johann et al., 2003). Among heroin-dependent patients, individuals carrying 5-HTTVNTR 10R allele or/and DATVNTR 9R allele are at higher risks of comorbid ASPD (Yang et al., 2012). On the other hand, individuals with 5-HTTVNTR 12R/12R and DATVNTR 10R/10R genotypes together are at lower risks of ASPD. Individuals with comorbid schizophrenia and cannabis abuse/dependence who are homozygous for rs12199654-A have smaller total cerebral and lobar white matter volumes. A comparative observational study revealed an allelic association between rs7103411 and comorbid alcohol dependence in a sample with primary schizophrenia. Allelic associations were also observed between both Brain Derived Neurotrophic Factor Gene Single nucleotide polymorphisms and comorbid alcohol dependence in the replication group. Haplotype analysis showed that the rs6265-rs7103411 A/C haplotype was associated with comorbid alcohol dependence (Cheah et al., 2014). Female heroin-dependent subjects with BPD had a lower frequency of the high-activity allele (L: 4 repeats [4R]) of MAOALPR when compared with those without BPD. In addition, they were found to have a higher 5-HTTVNTR 10R/10R genotype frequency than normal female controls (Yang et al., 2014). In a recent observational study, haplotypes of the rs183294 and rs209356 markers were significantly associated with history of suicide attempt as well as suicide specifier scores among individuals diagnosed with schizophrenia with suicidal behavior who had a history of alcohol abuse or dependence (Zai et al., 2014).

 

Most of the existing genetic studies have focused on the serotonergic and dopaminergic systems. However, the findings from individual studies remain largely unreplicated. Hence, it is difficult to draw conclusive inferences based on the existing evidence.

 

Studies on biomarkers/biochemicals/neuroreceptors

Growth hormone and beta-endorphin responses to clonidine are blunted among siblings of heroin-dependent subjects with personality disorders (Gerra et al., 1994). The genetic serotonergic impairment is unlikely to be involved in the pathogenesis of heroin dependence. However, it is likely to be associated with the presence of familial depression in comorbidity with heroin dependence. In addition, the GABAergic system is impaired only in heroin-dependent subjects with comorbid anxiety disorders and not among those with heroin dependence alone. Central hypodopaminergic state is associated with transient depressive symptoms observed among alcohol-dependent subjects undergoing detoxification. Subjects with alcohol dependence who commit suicide have a region-specific change in serotonin. Lifetime impulsivity and mood symptoms among subjects with alcohol dependence syndrome are associated with prefrontal cortex serotonin receptor mRNA levels (Thompson et al., 2012). Among individuals with comorbid substance use disorder and schizophrenia, improvement in substance use parameters is not associated with changes in endogenous cannabinoids. In addition, baseline anandamide levels predict endpoint substance-use-related scores among individuals with comorbid schizophrenia and substance use disorders. Monounsaturated N-acylethanolamines levels are also enhanced by comorbid mood and anxiety disorders in cocaine addicts. The magnitude of dopamine transporter blockade induced by methylphenidate in adolescents with comorbid ADHD and substance use disorders is comparable with that found in adolescents with ADHD alone (Szobot et al., 2008). Assessment of various cytokines among abstinent adults with cocaine use disorders categorized cocaine users into different subgroups with increased prevalence of comorbid psychiatric disorders (mood [54%], anxiety [32%], psychotic [30%], and personality [60%] disorders]. IL1[beta] was increased in users with psychiatric disorders relative to those users with no diagnosis (Araos et al., 2015).

 

Studies on neuroendocrinology

Studies in the area of neuroendocrinology of dual disorders have focused on individuals with depressive disorders and PTSD. The comorbid substance use disorders among these individuals have included opioid dependence and alcohol use disorders. Individuals with comorbid opioid dependence and depressive disorders have distinct responses to challenge with various biochemicals that are mediated through neurochemicals such as cortisol, growth hormone, and prolactin. Elevated total triiodothyronine among individuals with PTSD is not influenced by comorbid alcohol use disorder (Karlovic et al., 2004).

 

Limitations and Future Directions

There is limited published literature on neurobiology of dual disorders. Although the existing literature spans through various neurobiological domains, none of the comorbid substance use disorder and psychiatric disorder dyads have been studied extensively. The findings reported in individual studies remain largely nonreplicated. Hence, it is difficult to draw definitive conclusions based on findings of the published literature. Most of the studies have included relatively small sample size. Whereas a few of the studies have included female subjects and adolescents, most have included only adult men. Some of the studies have failed to include an appropriate control group. In addition, the interventional studies have failed to randomize the subjects. Diagnostic criteria for psychiatric disorders and substance use disorders also vary across the study as do the inclusion thresholds. Possible exposure to potential confounders could not be achieved in some interventional studies because of methodological limitations. The studies have made cross-sectional assessments during periods of active use or abstinence. The studies have failed to make prospective assessments over different phases of substance use. The investigations tools employed by most of the studies have limited exploratory and precision values. For example, the neuropathological studies employed nonspecific stains that could not distinguish between the various cell types.

 

There is a need to study various neurobiological aspects of dual disorders in greater detail. The future studies should assess various dual-disorder dyads in greater depths using more rigorous study designs. The studies should include diverse populations with larger sample sizes. The studies conducted among independent substance use disorders and psychiatric disorders could guide the future studies on dual disorders. This shall offer a much needed comparison between populations with isolated substance use disorders or psychiatric disorders and those with dual disorders. Such information shall help make more informed decisions for individuals with dual disorders. A more detailed understanding of the neurobiological aspects of dual disorders shall offer a substrate to explore effective interventions for those diagnosed with dual disorders.

 

REFERENCES

 

Araos P., Pedraz M., Serrano A., Lucena M., Barrios V., Garcia-Marchena N., Rodriguez de Fonseca F. (2015). Plasma profile of pro-inflammatory cytokines and chemokines in cocaine users under outpatient treatment: Influence of cocaine symptom severity and psychiatric co-morbidity. Addiction Biology, 20(4), 756-772. doi:10.1111/adb.12156 [Context Link]

 

Bourque J., Mendrek A., Durand M., Lakis N., Lipp O., Stip E., Potvin S. (2013). Cannabis abuse is associated with better emotional memory in schizophrenia: A functional magnetic resonance imaging study. Psychiatry Research, 214(1), 24-32. doi:10.1016/j.pscychresns.2013.05.012 [Context Link]

 

Cheah S. Y., Lawford B. R., Young R. M., Connor J. P., Phillip Morris C., Voisey J. (2014). BDNF SNPs are implicated in comorbid alcohol dependence in schizophrenia but not in alcohol-dependent patients without schizophrenia. Alcohol and Alcoholism, 49(5), 491-497. doi:10.1093/alcalc/agu040 [Context Link]

 

Cornelius J. R., Aizenstein H. J., Hariri A. R. (2010). Amygdala reactivity is inversely related to level of cannabis use in individuals with comorbid cannabis dependence and major depression. Addictive Behaviors, 35(6), 644-646. doi:10.1016/j.addbeh.2010.02.004 [Context Link]

 

De Bellis M. D., Narasimhan A., Thatcher D. L., Keshavan M. S., Soloff P., Clark D. B. (2005). Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders. Alcoholism, Clinical and Experimental Research, 29(9), 1590-1600. doi:00000374-200509000-00004 [pii] [Context Link]

 

Gerra G., Caccavari R., Marcato A., Zaimovic A., Avanzini P., Monica C., Brambilla F. (1994). Alpha-1- and 2-adrenoceptor subsensitivity in siblings of opioid addicts with personality disorders and depression. Acta Psychiatrica Scandinavica, 90(4), 269-273. [Context Link]

 

Gerra G., Caccavari R., Zaimovic A., Palladino M., Chittolini B., Giucastro G., Brambilla F. (1997). Serotonergic function in mothers of opioid addicts: Correlation with comorbid depression. Acta Psychiatrica Scandinavica, 96(1), 36-42. [Context Link]

 

Gerra G., Ferri M., Zaimovic A., Giucastro G., Palladino M., Sartori R., Brambilla F. (1998). GABAergic function in detoxified heroin addicts: Relationship to anxiety disorders. Psychiatry Research, 77(2), 89-96. doi:S0165-1781(97)00147-9 [pii] [Context Link]

 

Gerra G., Zaimovic A., Zambelli U., Delsignore R., Baroni M. C., Laviola G., Brambilla F. (2000). Neuroendocrine correlates of depression in abstinent heroin-dependent subjects. Psychiatry Research, 96(3), 221-234. doi:S0165-1781(00)00192-X [pii] [Context Link]

 

Gokturk C., Schultze S., Nilsson K. W., von Knorring L., Oreland L., Hallman J. (2008). Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism. Archives of Women's Mental Health, 11(5-6), 347-355. doi:10.1007/s00737-008-0033-6 [Context Link]

 

Hercher C., Parent M., Flores C., Canetti L., Turecki G., Mechawar N. (2009). Alcohol dependence-related increase of glial cell density in the anterior cingulate cortex of suicide completers. Journal of Psychiatry & Neuroscience, 34(4), 281-288. [Context Link]

 

Huang S. Y., Lu R. B., Ma K. H., Shy M. J., Lin W. W. (2008). Norepinephrine transporter polymorphisms T-182C and G1287A are not associated with alcohol dependence and its clinical subgroups. Drug and Alcohol Dependence, 92(1-3), 20-26. doi:S0376-8716(07)00241-4 [pii] [Context Link]

 

Johann M., Bobbe G., Putzhammer A., Wodarz N. (2003). Comorbidity of alcohol dependence with attention-deficit hyperactivity disorder: Differences in phenotype with increased severity of the substance disorder, but not in genotype (serotonin transporter and 5-hydroxytryptamine-2c receptor). Alcoholism, Clinical and Experimental Research, 27(10), 1527-1534. doi:10.1097/01.ALC.0000090143.00703.07 [Context Link]

 

Joyal C. C., Putkonen A., Mancini-Marie A., Hodgins S., Kononen M., Boulay L., Aronen H. J. (2007). Violent persons with schizophrenia and comorbid disorders: A functional magnetic resonance imaging study. Schizophrenia Research, 91(1-3), 97-102. doi:S0920-9964(06)00518-4 [pii] [Context Link]

 

Karlovic D., Marusic S., Martinac M. (2004). Increase of serum triiodothyronine concentration in soldiers with combat-related chronic post-traumatic stress disorder with or without alcohol dependence. Wiener Klinische Wochenschrift, 116(11-12), 385-390. [Context Link]

 

Lee S. Y., Hahn C. Y., Lee J. F., Huang S. Y., Chen S. L., Kuo P. H., Lu R. B. (2010). MAOA interacts with the ALDH2 gene in anxiety-depression alcohol dependence. Alcoholism, Clinical and Experimental Research, 34(7), 1212-1218. doi:10.1111/j.1530-0277.2010.01198.x [Context Link]

 

Linszen D. H., Dingemans P. M., Lenior M. E. (1994). Cannabis abuse and the course of recent-onset schizophrenic disorders. Archives of General Psychiatry, 51(4), 273-279. [Context Link]

 

Mancini-Marie A., Potvin S., Fahim C., Beauregard M., Mensour B., Stip E. (2006). Neural correlates of the affect regulation model in schizophrenia patients with substance use history: A functional magnetic resonance imaging study. The Journal of Clinical Psychiatry, 67(3), 342-350. [Context Link]

 

Mathalon D. H., Pfefferbaum A., Lim K. O., Rosenbloom M. J., Sullivan E. V. (2003). Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Archives of General Psychiatry, 60(3), 245-252. doi:yoa20509 [pii] [Context Link]

 

Miguel-Hidalgo J. J., Overholser J. C., Meltzer H. Y., Stockmeier C. A., Rajkowska G. (2006). Reduced glial and neuronal packing density in the orbitofrontal cortex in alcohol dependence and its relationship with suicide and duration of alcohol dependence. Alcoholism, Clinical and Experimental Research, 30(11), 1845-1855. doi:ACER221 [pii] [Context Link]

 

Miguel-Hidalgo J. J., Wei J., Andrew M., Overholser J. C., Jurjus G., Stockmeier C. A., Rajkowska G. (2002). Glia pathology in the prefrontal cortex in alcohol dependence with and without depressive symptoms. Biological Psychiatry, 52(12), 1121-1133. doi:S0006322302014397 [pii] [Context Link]

 

Miller F., Barasch A., Sacks M., Levitan J., Ashcroft L. (1986). Serum prolactin correlates with depressed mood during alcohol withdrawal. Drug and Alcohol Dependence, 17(4), 331-338. [Context Link]

 

Nellissery M., Feinn R. S., Covault J., Gelernter J., Anton R. F., Pettinati H., Kranzler H. R. (2003). Alleles of a functional serotonin transporter promoter polymorphism are associated with major depression in alcoholics. Alcoholism, Clinical and Experimental Research, 27(9), 1402-1408. doi:10.1097/01.ALC.0000085588.11073.BB [Context Link]

 

Onwuameze O. E., Nam K. W., Epping E. A., Wassink T. H., Ziebell S., Andreasen N. C., Ho B. C. (2013). MAPK14 and CNR1 gene variant interactions: Effects on brain volume deficits in schizophrenia patients with marijuana misuse. Psychological Medicine, 43(3), 619-631. doi:10.1017/S0033291712001559 [Context Link]

 

Pavon F. J., Araos P., Pastor A., Calado M., Pedraz M., Campos-Cloute R., Rodriguez de Fonseca F. (2013). Evaluation of plasma-free endocannabinoids and their congeners in abstinent cocaine addicts seeking outpatient treatment: Impact of psychiatric co-morbidity. Addiction Biology, 18(6), 955-969. doi:10.1111/adb.12107 [Context Link]

 

Pierucci-Lagha A., Feinn R., Modesto-Lowe V., Swift R., Nellissery M., Covault J., Kranzler H. R. (2004). Effects of rapid tryptophan depletion on mood and urge to drink in patients with co-morbid major depression and alcohol dependence. Psychopharmacology (Berlin), 171(3), 340-348. doi:10.1007/s00213-003-1588-6 [Context Link]

 

Potvin S., Kouassi E., Lipp O., Bouchard R. H., Roy M. A., Demers M. F., Stip E. (2008). Endogenous cannabinoids in patients with schizophrenia and substance use disorder during quetiapine therapy. Journal of Psychopharmacology, 22(3), 262-269. doi:10.1177/0269881107083816 [Context Link]

 

Potvin S., Mancini-Marie A., Fahim C., Mensour B., Stip E. (2007). Processing of social emotion in patients with schizophrenia and substance use disorder: An fMRI study. Social Neuroscience, 2(2), 106-116. doi:10.1080/17470910701376787 [Context Link]

 

Sameti M., Smith S., Patenaude B., Fein G. (2011). Subcortical volumes in long-term abstinent alcoholics: Associations with psychiatric comorbidity. Alcoholism, Clinical and Experimental Research, 35(6), 1067-1080. doi:10.1111/j.1530-0277.2011.01440.x [Context Link]

 

Scheller-Gilkey G., Lewine R. R., Caudle J., Brown F. W. (1999). Schizophrenia, substance use, and brain morphology. Schizophrenia Research, 35(2), 113-120. doi:S0920-9964(98)00096-6 [pii] [Context Link]

 

Schiffer B., Muller B. W., Scherbaum N., Forsting M., Wiltfang J., Leygraf N., Gizewski E. R. (2010). Impulsivity-related brain volume deficits in schizophrenia-addiction comorbidity. Brain, 133(10), 3093-3103. doi:10.1093/brain/awq153 [Context Link]

 

Singh S., Balhara Y. P. (2016). A review of Indian research on co-occurring psychiatric disorders and alcohol use disorders. Indian Journal of Psychological Medicine, 38(1), 10-19. doi:10.4103/0253-7176.175089 [Context Link]

 

Sullivan E. V., Rosenbloom M. J., Serventi K. L., Deshmukh A., Pfefferbaum A. (2003). Effects of alcohol dependence comorbidity and antipsychotic medication on volumes of the thalamus and pons in schizophrenia. The American Journal of Psychiatry, 160(6), 1110-1116. [Context Link]

 

Swofford C. D., Kasckow J. W., Scheller-Gilkey G., Inderbitzin L. B. (1996). Substance use: A powerful predictor of relapse in schizophrenia. Schizophrenia Research, 20(1-2), 145-151. doi:0920-9964(95)00068-2 [pii] [Context Link]

 

Szobot C. M., Shih M. C., Schaefer T., Junior N., Hoexter M. Q., Fu Y. K., Rohde L. A.(2008). Methylphenidate DAT binding in adolescents with attention-deficit/ hyperactivity disorder comorbid with substance use disorder-A single photon emission computed tomography with [Tc(99m)]TRODAT-1 study. Neuroimage, 40(3), 1195-1201. doi:10.1016/j.neuroimage.2007.12.050 [Context Link]

 

Thompson J. L., Urban N., Slifstein M., Xu X., Kegeles L. S., Girgis R. R., Abi-Dargham A. (2013). Striatal dopamine release in schizophrenia comorbid with substance dependence. Molecular Psychiatry, 18(8), 909-915. doi:10.1038/mp.2012.109 [Context Link]

 

Thompson P. M., Cruz D. A., Olukotun D. Y., Delgado P. L. (2012). Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide. Acta Psychiatrica Scandinavica, 126(3), 165-174. doi:10.1111/j.1600-0447.2011.01816.x [Context Link]

 

Verhagen M., van der Meij A., Janzing J. G., Arias-Vasquez A., Buitelaar J. K., Franke B. (2009). Effect of the 5-HTTLPR polymorphism in the serotonin transporter gene on major depressive disorder and related comorbid disorders. Psychiatric Genetics, 19(1), 39-44. doi:10.1097/YPG.0b013e3283208061 [Context Link]

 

Wittchen H. U. (1996). Critical issues in the evaluation of comorbidity of psychiatric disorders. The British Journal of Psychiatry. Supplement, (30), 9-16. [Context Link]

 

Woodward S. H., Kaloupek D. G., Streeter C. C., Kimble M. O., Reiss A. L., Eliez S., Arsenault N. J. (2006). Hippocampal volume, PTSD, and alcoholism in combat veterans. The American Journal of Psychiatry, 163(4), 674-681. doi:163/4/674 [pii] [Context Link]

 

Yang M., Kavi V., Wang W., Wu Z., Hao W. (2012). The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and antisocial personality disorder in male heroin-dependent Chinese subjects. Progress in Neuro-psychopharmacology & Biological Psychiatry, 36(2), 282-289. doi:10.1016/j.pnpbp.2011.11.009 [Context Link]

 

Yang M., Mamy J., Wang Q., Liao Y. H., Seewoobudul V., Xiao S. Y., Hao W. (2014). The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and borderline personality disorder in female heroin-dependent Chinese subjects. Progress in Neuro-psychopharmacology & Biological Psychiatry, 50, 74-82. doi:10.1016/j.pnpbp.2013.12.005 [Context Link]

 

Zai C. C., Zai G. C., Tiwari A. K., Manchia M., de Luca V., Shaikh S. A., Kennedy J. L. (2014). Association study of GABRG2 polymorphisms with suicidal behaviour in schizophrenia patients with alcohol use disorder. Neuropsychobiology, 69(3), 154-158. doi:10.1159/000358839 [Context Link]

 

Zammit S., Spurlock G., Williams H., Norton N., Williams N., O'Donovan M. C., Owen M. J. (2007). Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: Interactions with tobacco and cannabis use. The British Journal of Psychiatry, 191, 402-407. doi:191/5/402 [pii] [Context Link]