REVIEW

CURRENT
OPINION Treatment of dual diagnosis disorders
Pratima Murthy and Prabhat Chand

Purpose of review
Treatment of dual diagnosis [co-occurrence of a substance use disorder (SUD) in patients with mental
illness] poses several challenges for mental health professionals. This article seeks to review the recent
advances in dual diagnosis treatment with respect to pharmacotherapy and psychosocial approaches.
Recent findings
Atypical antipsychotics are commonly used for comorbid schizophrenia and SUD. Whereas there is no
difference between risperidone and olanzapine, clozapine appears to have a distinct advantage in
reducing psychotic symptoms as well as substance abuse (including smoking). There is emerging evidence
that quetiapine is beneficial in dually diagnosed patients, particularly using alcohol, cocaine and
amphetamine. A combination of naltrexone and sertraline was found to be effective in patients with
depressive disorder and alcohol dependence. Effectiveness of atomoxetine is yet to be established in
patients with comorbid adult attention-deficit/hyperactivity disorder with respect to decrease in substance
abuse. Integrated intervention is the choice of treatment for patients with dual diagnosis.
Summary
In spite of the high association between substance use and psychiatric disorders, there is a surprising
paucity of studies related to treatment and outcome. A few well-designed studies have been recently
published and more studies of this nature are required in order to address the challenges posed in the
treatment of dual disorders.
Keywords
dual diagnosis, psychiatric disorder, substance use, treatment

INTRODUCTION and addiction as well as psychiatric disorders in

Dual diagnosis is traditionally defined as the co- recent times. This, along with the development
occurrence of substance use disorder (SUD) in of newer pharmacotherapies and integrated models
patients with severe mental illness, that is of intervention, has placed us in a relatively better
schizophrenia and bipolar disorder. In recent times, position to address treatment issues in dual diag-
the notion of dual diagnosis has been expanded nosis than earlier. This is also reflected by the
and used interchangeably with comorbid or co- increasing number of excellent reviews on treat-
occurring disorders, that is, occurrence of any ment that have been published in recent times
&
&
mental illness along with an SUD [1 ,2,3]. Mental [1 ,8–10]. In our review, the major focus will be
health professionals frequently find the treatment recent research on treatment of substance use in
of dually diagnosed patients challenging and diffi- schizophrenia and bipolar disorder. In the latter part
cult. Although about 50% of patients with severe of the article, we briefly mention treatment issues in
mental illness have substance use and vice versa, the other comorbid psychiatric disorders.
treatment aspect is compounded by lack of clarity
about pharmacotherapy, psychological interven-
tions, setting of treatment and so on [4]. In devel-
Department of Psychiatry, National Institute of Mental Health and Neuro-
oping countries like India, where the prevalence of
sciences (NIMHANS), Bangalore, India
substance use in the general community is relatively
Correspondence to Professor Pratima Murthy, Professor of Psychiatry
lower, the extent of comorbidity, particularly with and Chief, Centre for Addiction Medicine, National Institute of Mental
&
illicit drugs, is also lower [5 ,6,7]. Thus, current Health and Neurosciences (NIMHANS), Hosur Road, Bangalore
literature in this area is evident largely from the 560029, India. Tel: +91 80 26995274; e-mail: pratimamurthy@gmail.
developed countries. com
There has been a greater understanding of the Curr Opin Psychiatry 2012, 25:194–200
neurobiology, including genetics, of substance use DOI:10.1097/YCO.0b013e328351a3e0

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 Treatment of dual diagnosis disorders Murthy and Chand

substance abuse. These studies have demonstrated

KEY POINTS that the likely rate of decrease in substance use is

Atypical antipsychotics, including clozapine, are about 70–80% and the benefit also continues at
preferred agents in patients with comorbid psychotic long-term follow-up [12,14]. Such a finding needs
disorders. to be validated by a randomized controlled trial.
There has been a study comparing the efficacy

Apart from valproate, preliminary findings suggest the
of olanzapine and risperidone among patients
effectiveness of quetiapine in bipolar patients with
substance use disorders (SUDs). with first episode schizophrenia, schizophreniform
or schizoaffective disorder and comorbid lifetime

Selective serotonin reuptake inhibitors (SSRIs) in cannabis use disorder. Forty-nine patients were ran-
combination with anticraving agents, i.e. sertraline– domly assigned to treatment with either risperidone
naltrexone combination, were found useful in patients
(n ¼ 21) or olanzapine (n ¼ 28). Out of those,
with major depression and alcohol dependence.
29 patients had recent use of cannabis, that is in

There is a paucity of treatment research in dual the last 3 months, 19 patients had lifetime history of
disorders across the world, more so from developing alcohol use disorders and seven patients had other
countries. lifetime SUDs. At the end of 16 weeks of treatment,
there was available information for 16 patients on
risperidone and 21 patients on olanzapine. There
was no statistical difference in use of cannabis or
SCHIZOPHRENIA AND PSYCHOTIC alcohol among the groups between 8 and 16 weeks
DISORDERS of treatment. There was no difference in cannabis
The lifetime association of schizophrenia with SUD use during the treatment period between current
is very high. Persons with schizophrenia have an cannabis users (within 3 months) and lifetime users.
odds ratio of 3.3 for developing alcohol abuse or The study showed that olanzapine is not superior
dependence and of 6.2 for developing other SUDs to risperidone in the treatment of co-occurring
[11,12]. The most common SUDs associated are cannabis use disorder and both medicines improved
&
alcohol, cannabis and cocaine, apart from nicotine. positive symptoms of schizophrenia [15 ]. The
limitation of the study, which is a secondary
analysis, is its small sample size, thereby limiting
Pharmacological the power of the study and its interpretation.
The second-generation antipsychotics are preferred Although the second-generation antipsychotics
medications in view of fewer side effects, particu- are reportedly beneficial in reducing craving for
larly extrapyramidal symptoms (EPS). In one study, substances, there are differences in the anticraving
36 schizophrenia patients with comorbid substance effects between different medications. This differ-
abuse were compared with 41 patients without sub- ential response may be due to the differences in
stance use. There was a third group (38 patients), occupancy as well as dissociation of D2 receptors.
who were only substance abusers undergoing detox- Clozapine has low affinity, whereas risperidone
ification. The comorbid schizophrenia group scored has high affinity (comparable to haloperidol) to
&&
significantly higher in parkinsonian symptoms than the D2 receptor [16 ]. As part of a naturalistic
the group without substance abuse as measured cohort genetic risk and outcome study, Machielsen
&&
by the Extrapyramidal Symptoms Rating Scale et al. [16 ] compared the effect of three atypical
and the Barnes Akathisia Scale. Patients with antipsychotics, risperidone, olanzapine and cloza-
schizophrenia who were abusing/dependent on pine, on subjective craving among patients with
cocaine and alcohol had more parkinsonian cannabis dependence and nonaffective psychosis
symptoms. The third group with substance abuse (schizophrenia, schizophreniform disorder, schizo-
(without schizophrenia) were also found to have affective disorder, delusional disorder, psychotic
more akathisia than those with schizophrenia. disorder not otherwise specified). The mean dose
The authors propose that substance abuse itself of risperidone was 3.46 mg (SD ¼ 1.62), olanzapine
can contribute to EPS in individuals with and with- 13.78 mg (SD ¼ 6.725) and clozapine 350 mg (SD ¼
out schizophrenia [12,13]. 166.58). Patients on risperidone reported signifi-
Antipsychotics, by virtue of their dopaminergic cantly more craving compared with the other two
action on the mesocorticolimbic pathway, should groups. There was no difference in craving between
potentially influence substance use quite apart the olanzapine and clozapine groups. A limitation of
from their antipsychotic actions. Findings from the study is that the differences in craving scores
retrospective studies and case reviews indicate that were not maintained when a different subscale
&&
clozapine is an effective drug for both psychosis and (craving) was used [16 ]. Similar increase in craving

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 Addictive disorders

as well as dependence has been reported for nicotine and/or illicit substance use, quality of life and
among patients treated with risperidone [17]. overall functioning 3 months after baseline. The
The beneficial effects of anticraving agents follow-up assessments were done four times in the
like acamprosate, naltrexone, topiramate, among next year. At the end of 3 months the integ-
others, on substance use are yet to be established rated treatment group showed highly significant
in the dually diagnosed patient. There is a lack of improvement in drug use and addiction severity.
research in this area, although these agents are used The improvement in alcohol use was also close
commonly in practice [18]. One study examined to significant in the integrated treatment group
the effect of acamprosate on cognition in patients (P ¼ 0.052). Although both the groups showed
with schizophrenia and alcohol dependence. The improvement in psychiatric symptomatology, the
assumption is that both the disorders are associated treatment as usual group did not show improve-
with deficits in cognitive functions, particularly of ment in positive symptoms as measured by Positive
a prefrontal nature. Acamprosate, an N-methyl-D- and Negative Syndrome Scale. There was a high
aspartate (NMDA) modulator, is likely to improve drop-out at the end of 1 year in both the groups.
cognitive function and thereby change drinking Maximum attrition occurred at the end of 3 months.
patterns. In this study, 23 patients were randomized Twelve out of 85 and seven out of 35 completed the
to either acamprosate or placebo for a period of year in the integrated and treatment as usual groups
12 weeks. Fifteen (65%) completed the treatment. respectively. The drop-out rate was significant in the
Overall drinking had decreased in both the groups treatment as usual group after 3 months. At the end
compared with baseline, and acamprosate was not of 6 months and 1 year, most of the improvements
&&
found superior to placebo. Although there was a were maintained [21 ].
decrease in psychotic symptoms, there was neither There is growing evidence of the effectiveness
improvement nor worsening in cognitive function of psychological interventions among dually
at the end of the study. In spite of the small number, diagnosed patients. The most effective specific inte-
limited time period, and high drop-outs, among grated interventions for substance abuse in patients
other things, as well as a negative finding, this study with schizophrenia include group counselling
also showed that acamprosate is relatively well along with cognitive–behavioral and motivational
tolerated in patients with cognitive deficits, as there components [22]. A recent randomized controlled
&&
was no further cognitive worsening [19 ]. trial has looked at effectiveness of integrated
motivational interviewing and cognitive behavior
therapy (CBT) along with standard care, compared
Nonpharmacological with standard care alone, among patients with
In many contemporary treatment settings, mental psychosis and substance abuse or dependence.
health and substance use services are provided Three hundred and twenty-seven participants were
separately. Thus, patients with dual diagnosis are randomly allocated to either the intervention
advised to get treated in one system for one disorder (n ¼ 164) or treatment as usual (n ¼ 163), and the
and then referred to the other system. Sometimes intervention consisted of 26 individual sessions for
two sets of experts, that is, mental health and 12 months, which were provided at their home.
substance experts, evaluate such patients independ- At the end of 24 months, 326 patients could be
ently. Such models delay initiation of the appro- reassessed. There was no significant difference in
priate interventions and also add to the burden of the primary outcome, that is, admission to hospital
healthcare resources. In contrast, in the multi- for a reason related to psychosis or death from any
disciplinary ‘integrated treatment’ approach, the cause in both the groups. A higher proportion of
same clinicians working in one setting provide both patients from the integrated intervention group
mental health and substance use interventions were admitted during the follow-up period.
which are tailor-made for the dually diagnosed Similarly, there was no difference in secondary out-
patient. This consists of the use of medications for come, that is, number of abstinent days, between
both mental illness and substance use, coordinated the groups with respect to the main substance or
psychotherapy, psychosocial treatments for mental other substances of abuse. However, the integrated
illness and substance use matching the patient’s treatment group had a significantly lower amount
motivation [8,20]. of substance use on substance-using days. One
In an open nonrandomized study, patients with important finding from the study is that it is possible
schizophrenia and comorbid SUDs were divided to keep patients engaged in 26 sessions over a period
into two groups, integrated treatment and treat- of 1 year and thereby improve patients’ motivation
ment as usual. Patients were followed up for 1 year to change substance use. This benefit could, how-
and assessed for psychiatric symptoms, alcohol ever, not be sustained over the next year. This study

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 Treatment of dual diagnosis disorders Murthy and Chand

highlights the fact that CBT and motivational a high drop-out rate and only 26 out of 50 patients
interviewing, which have been shown to be success- could be assessed at the end of the study. Although
ful in bringing a change in primary SUDs, have there was a decrease in alcohol drinking among
partial benefit in the treatment of dual diagnosis patients on naltrexone than placebo, this was not
[23]. significant. Similar results without statistical signifi-
cance (i.e. a beneficial trend for the naltrexone
group) were seen for drinking days and craving
MOOD DISORDERS scores. Gamma glutamyl transferase did not show
The US National Comorbidity Survey data indicate any difference between the two groups [36].
high coexistence of bipolar disorder with SUDs [24]. Antidepressants are reported to improve
Almost half of bipolar patients have an alcohol depressive symptoms by 75%, whereas they reduce
problem in their lifetime. drinking by only 30% in patients with major
depressive disorder [37]. In spite of the high comor-
bidity of depression and alcohol abuse, there is a lack
Pharmacological of well-designed studies in this area. A combination
Effectiveness of valproate or divalproex sodium has of antidepressant and anticraving agent, sertraline
been shown in different randomized controlled and naltrexone, was used in patients with major
trials (RCTs), and this is currently the drug of choice depression and alcohol dependence. In a 14-week
for bipolar disorder with comorbid substance use study, 170 patients were randomly assigned to
[25–27]. There is a lack of studies regarding use of one of the following four treatment conditions:
other mood stabilizers like lamotrigine, topiramate sertraline and naltrexone (N ¼ 42); naltrexone and
and gabapentin in dually diagnosed patients. placebo (N ¼ 49); sertraline and placebo (N ¼ 40); or
Among atypical antipsychotics, there is growing double placebo (N ¼ 39). The dosage of sertraline
evidence of the usefulness of quetiapine in primary was 200 mg per day and that of naltrexone was
alcohol, cocaine, opioid and other SUDs [28,29]. 100 mg per day, on the higher side of the prescribed
Recently, there is also growing evidence of quetia- therapeutic dose. Patients received weekly CBT
pine abuse, more so in patients with multiple SUDs sessions. Forty-three percent of patients prematurely
[30–32]. Although quetiapine is an approved agent discontinued treatment and, on average, a patient
for independent bipolar disorder, its effectiveness in attended 8.2 individual CBT sessions. Patients on
case of comorbid substance abuse is yet to be estab- combined medications had significantly greater
lished. In a small open-label study (n ¼ 28, 16 bipolar total abstinence (53.7%) compared with all other
patients), quetiapine significantly decreased alcohol groups combined. The combined medication
consumption (43% of patients remained totally group was significantly better with respect to heavy
alcohol-free for the duration of the study), craving drinking and time to relapse of heavy drinking.
for alcohol and psychiatric symptom intensity [33]. All the groups had clinically significant reduction
In a large (n ¼ 362) placebo-controlled, randomized
&
in depressive symptoms [38 ].
study among bipolar I disorder with comorbid
alcohol dependence, quetiapine was used an
adjunct to lithium or divalproex for reduction in NONPHARMACOLOGICAL
alcohol drinking. Quetiapine was prescribed up to Studies have shown that addition of CBT and
400 mg per day for the first week and thereafter at a motivational interviewing to standard care is
flexible dosage between 300 and 800 mg per day till beneficial in patients with SUDs and depression.
the end of the study period, that is, 12 weeks. There Young patients with depression and SUDs received
was no significant change in mean heavy drinking either standard care or CBT/motivational inter-
period, time to first consecutive 2 weeks of absti- viewing in addition to standard care. The pro-
nence, proportion of nondrinking days, or clinical portion of patients with SUDs was significantly
global improvement between placebo and quetia- lower in the intervention group at 3 months
pine at the end of the study [34]. Quetiapine could and 6 months of follow-up. Apart from decreased
significantly decrease depressive symptoms, but not cannabis use, there was no change in frequency and
alcohol use, in patients with bipolar disorder and quantity of alcohol or other substance use during
alcohol dependence [35]. follow-up. Patients who received psychological
There are few studies on the effect of medi- interventions achieved a significantly greater rate
cations used for substance abuse in dual-disordered of change in depression, cannabis use, motivation
populations. A double-blind RCT for 12 weeks to change and social contacts faster than that of
compared naltrexone and placebo in patients with standard care. At the end of 6 months, both the
bipolar disorder and alcohol dependence. There was groups had similar improvements. This study

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 Addictive disorders

&
showed partial benefit of integrated CBT/motiva- marijuana use at the end of the study [45 ]. In adult
tional interviewing intervention in young comor- ADHD patients with substance use, the addition of
&&
bid patients [39 ]. atomoxetine appeared to bring improvement in
clinician-rated ADHD, but not in self-reported
ADHD symptoms or substance use.
ANXIETY DISORDERS
The recent and largest comorbid survey in the USA,
the National Epidemiological Survey on Alcohol NICOTINE USE DISORDERS
and Related Conditions (NESARCs), reports that Surprisingly, there is very limited literature for the
17.7% of persons with current SUD also fulfil criteria treatment of nicotine dependence with comorbid
for anxiety disorder [40]. It is often difficult to psychiatric disorders in spite of its very high pre-
distinguish anxiety symptoms from withdrawal valence. This has been described as ‘silent dual
features of substances. Prolonged observation diagnosis’ [4]. The benefit of varenicline has been
during a substance-free period is essential to confirm described in a recent study. Patients who had lower
the diagnosis. affective flattening, as measured by Scale for the
Benzodiazepines are effective in anxiety Assessment of Negative Symptoms at baseline, were
disorders, but the risk of abuse liability is very high more successful in smoking cessation with the help
in patients with SUDs. Selective serotonin reuptake of varenicline and CBT. These patients also had
inhibitors (SSRIs) and serotonin norepinephrine more improvement in reward responsiveness during
&
reuptake inhibitors are generally considered first- the treatment [46 ]. At the same time, there are
line therapy. CBT in combination with anti- reports of exacerbation of psychosis and worsening
depressants has most evidence-based support [41]. of mood symptoms with varenicline.
In recent times most of the studies are published
with respect to effectiveness of SSRIs and psycho-
logical treatments in post-traumatic stress disorder CONCLUSION
and comorbid substance use. The article by Back and Treatment of dual disorders continues to pose
Brady provides an excellent review in this regard difficulties and challenges to mental health pro-
[42]. fessionals. The recent experience from developed
country settings, where mental illness and SUDs
often coexist, suggests that integrated models of
ATTENTION DEFICIT/ HYPERACTIVITY intervention are more likely to be beneficial
DISORDER and reduce treatment costs. In the treatment of
Adult attention deficit disorder (ADD) is commonly schizophrenia with comorbid substance use, the risk
associated with a higher risk of substance use, of parkinsonian symptoms with antipsychotic treat-
particularly in young populations. A trial with ment is greater. There are preliminary findings
atomoxetine has shown improvement in ADD suggesting the effectiveness of clozapine in reducing
symptoms but inconsistent drinking outcomes psychotic symptoms and substance use. Such find-
[43]. In a 12-week RCT, 70 adolescents with diag- ings have not been demonstrated with the use of
nosed attention deficit hyperactivity disorder risperidone, the use of which, in fact, has been
(ADHD) and SUD (nontobacco) received either associated with increased craving. The beneficial
atomoxetine or placebo. All participants received effect of combining antipsychotic and anticraving
weekly individual motivational interviewing/CBT. agents is yet to be studied. The use of psychological
There was no significant difference in either the interventions using cognitive behavior and
substance use pattern or the ADHD scores between motivation-enhancing strategies in patients with
the two groups. Both groups had significant before schizophrenia and substance use has shown partial
and after decrease in ADHD scores [44]. Another benefit in the treatment of dual disorders. In the
similar 12-week RCT study was done in marijuana- case of mood disorders with comorbid substance
dependent adults with ADHD. The participants use, although there is some suggestion that quetia-
received either atomoxetine or placebo apart from pine may reduce alcohol consumption and craving
motivational interviewing for substance use. Out of while ameliorating the psychiatric symptom inten-
46 patients who were randomized (1 : 1) to two sity, particularly when used as an adjunct to lithium
groups, 38 participants came for at least one inter- or divalproex, this has not been replicated. One
view and 16 completed 12 weeks of intervention. study reported a beneficial trend for naltrexone
There was significant improvement in clinician- compared with placebo in patients with bipolar
rated ADHD symptoms, but no improvement disorder and alcohol dependence. In major depress-
was seen in self-reported ADHD symptoms and ive disorder with alcohol abuse, a combination of

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 Treatment of dual diagnosis disorders Murthy and Chand

15. Sevy S, Robinson DG, Sunday S, et al. Olanzapine vs. risperidone in patients
naltrexone and sertraline, along with weekly CBT, & with first-episode schizophrenia and a lifetime history of cannabis use dis-
produced greater total abstinence compared with orders: 16-week clinical and substance use outcomes. Psychiatry Res 2011;
188:310–314.
either drug alone or placebo. Partial benefit of The result of this study showed that olanzapine and risperidone have equal efficacy of
integrated CBT/motivational interviewing interven- response to psychotic symptoms, cannabis and alcohol use at the end of 16 weeks.
16. Machielsen M, Scheltema Beduin A, Dekker N, et al. Differences in craving for
tion has been shown in young patients with major && cannabis between schizophrenia patients using risperidone, olanzapine or
depression and substance use. clozapine. J Psychopharmacol 2012; 26:189–195.
Authors have assessed subjective craving among three atypical antipsychotics in
There is a continuing need for treatment effec- patients of schizophrenia with cannabis dependence. Patients on risperidone
tiveness research in dual diagnosis. For developed reported more subjective craving. The result is in accordance with the differential
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 Addictive disorders

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