REVIEW

CURRENT
OPINION Treatment of substance use disorders with
co-occurring severe mental health disorders
Pratima Murthy, Jayant Mahadevan, and Prabhat K. Chand

Purpose of review
To provide an update of treatment for substance use in patients with co-occurring substance use disorders
(SUD) and mental health disorders (dual diagnosis) with a focus on both pharmacological and
psychosocial interventions.
Recent findings
A total of 1435 abstracts were identified, of which we selectively reviewed 43 for this narrative review. There
is emerging evidence, both clinical and neurobiological, that clozapine is a more efficacious antipsychotic in
treatment of individuals with schizophrenia and SUD. The use of depot atypical antipsychotic paliperidone
palmitate in this population is also promising. Although valproate remains the treatment of choice in
individuals with bipolar disorder and SUD, present evidence suggests that lithium and quetiapine may not be
effective in this population. Naltrexone is the most effective anticraving agent in individuals with severe mental
illness (SMI) and comorbid alcohol use disorders. The use of opioid substitution therapy in individuals with
SMI and comorbid opioid use disorders is also associated with favorable outcomes. Varenicline shows
promise in patients with SMI who smoke tobacco. Psychosocial interventions should be instituted early in the
course of treatment. They should ideally be high intensity and based on established therapies used for SUD.
Summary
The paucity of systematic studies in individuals with co-occurring mental health disorders and SUD remains
a concern, given the enormous burden that they pose. However, there are a number of studies which have
evaluated interventions, both psychosocial and pharmacological, which show promise and can guide
clinical practice.
Video abstract
http://links.lww.com/YCO/A49.
Keywords
bipolar mood disorder, co-occurring disorders, dual diagnosis, mental health disorder, schizophrenia, substance
use, treatment

INTRODUCTION on treatment, generally tend to exclude patients with

Co-occurring substance use and mental health disor-
ders (dual diagnosis) commonly refers to substance use
in severe mental disorders (schizophrenia, schizophre-
nia spectrum disorders, bipolar mood disorders and
depressive disorders) [1]. A recently published meta-
analysis shows that 41% of individuals with schizo-
phrenia spectrum disorders [2] and 33% with bipolar
mood disorders [3] have co-occurring substance use
disorders (SUD). SUD also co-occur with other mental
health disorders including anxiety disorders [4], post-
traumatic stress disorders (PTSDs) [5], externalizing
disorders such as attention deficit hyperactivity disor-
der and personality disorders [6], in which they may be
under-recognized and undertreated.
Randomized control trials (RCTs) in both SUD
and mental health disorders, especially those focusing
co-occurring severe mental disorders. Research in this
field thus comprises largely of retrospective data anal-
yses or naturalistic follow-up studies from settings in
which patients with co-occurring disorders are
treated. This review will update a previous review in
the area [7] by summarizing recent research on
Department of Psychiatry, Centre for Addiction Medicine, National Insti-
tute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, India
Correspondence to Dr Pratima Murthy, Professor of Psychiatry and
Head, Department of Psychiatry, Centre for Addiction Medicine, National
Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore
560029, India. Tel: +91 8026995274;
e-mail: pratimamurthy@gmail.com
Curr Opin Psychiatry 2019, 32:293–299
DOI:10.1097/YCO.0000000000000510

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Addictive disorders
KEY POINTS
 Clozapine may be more efficacious than other
antipsychotics in individuals with schizophrenia and
comorbid SUD.
 Valproate may be preferred over lithium and
quetiapine in individuals with bipolar disorders and
comorbid SUD.
 Naltrexone is useful as an anticraving agent in
individuals with dual diagnosis.
 Varenicline is well tolerated and efficacious for
individuals with SMI and nicotine dependence.
 Psychosocial interventions should start early in the
course of treatment for individuals with dual diagnosis.
pharmacological and psychosocial approaches for
management of patients with co-occurring severe
mental illness (SMI) and SUD.
This is a narrative review which searched data-
bases such as PubMed, EMBASE, PsycInfo, Google
Scholar for articles published between 1 January
2017 and 31 January 2019 on treatment of patients
with mental illness and SUD. The article types include
reviews (systematic and narrative), meta-analyses,
RCTs (blinded and open label), cohort and case–con-
trol studies, as well as secondary analyses of epidemi-
ological and clinical data. We identified a total of 1435
abstracts published in this window period from which
we identified 78 full text articles and finally included
43 relevant articles for this review.
GENERAL PRINCIPLES FOR
MANAGEMENT
An integrated approach for individuals with co-
occurring disorders is the presently preferred
approach in many treatment guidelines. This
approach requires adequate human resources and
infrastructure, still not available in many parts of the
world. However, a recent evaluation of an integrated
dual diagnosis treatment program for outpatients in
the Netherlands (which used a randomized con-
trolled stepped-wedge cluster design in six assertive
community treatment teams), found that although
there was an overall reduction in the number of days
of alcohol or drug use, there were no improvements
on other secondary outcomes such as psychopathol-
ogy, functioning, therapeutic alliance or motivation
to change. There was also no improvement in
trained clinicians’ knowledge, attitudes or motiva-
tional interviewing skills which was speculated to be
the reason for lack of improvement in secondary
&
outcomes [8 ].
294 www.co-psychiatry.com
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In the subsequent sections, pharmacological
approaches are first discussed, followed by psycho-
social approaches in specific disorders.
PHARMACOLOGICAL MANAGEMENT
This section reviews the impact of antipsychotics on
substance use outcome and the utility of anticraving
agents in co-occurring severe mental health disorders.
SCHIZOPHRENIA AND SCHIZOPHRENIA
SPECTRUM DISORDERS
In a recent survey among Italian psychiatrists about
prescribing practices in co-occurring disorders, the
atypical antipsychotics aripiprazole and olanzapine
were the most preferred agents for acute and main-
tenance treatment. Depot antipsychotics were also
used by about 50% of practitioners [9]. This is con-
sistent with practice and guidelines from different
parts of the world.
Open label trials and randomized controlled
trials have demonstrated the comparative efficacy
of olanzapine, clozapine and risperidone over other
antipsychotics or treatment as usual (TAU) with
respect to substance use outcomes such as reduc-
tions in positive urine screens and number of days of
&
use [10 ]. Second generation antipsychotics are pre-
ferred because of a lower likelihood of extra pyrami-
dal side-effects [11]. However, a recent meta-analysis
of randomized controlled trials which included
1073 patients and compared risperidone with cloza-
pine, olanzapine, perphenazine, quetiapine and
ziprasidone in individuals with dual diagnosis found
no differences between antipsychotics with respect
to reduction in positive symptoms, reduction in
substance (cannabis) use or extrapyramidal side
effects. An exception is clozapine which was found
to have an impact on reduction in craving for can-
&&
nabis [12 ]. In a small retrospective case–control
study in adolescents with psychosis and cannabis
use disorder, clozapine treatment led to decreased
cannabis use and severity of psychotic symptoms
compared with treatment with other antipsychotics
[13]. A recent functional magnetic resonance imag-
ing study in individuals with schizophrenia and
cannabis use disorder compared the effect of cloza-
pine and risperidone on subjective craving and brain
activation during a cue reactivity task. The clozapine
group had a greater reduction in subjective craving
for cannabis and larger decreases in amygdalar acti-
vation during exposure to cannabis-related images
&&
of a cue reactivity paradigm [14 ]. Clozapine’s effect
in reducing craving is attributed to its relatively
lower affinity for and rapid dissociation from D2
dopamine receptors [15]. Aripiprazole, a partial
Volume 32  Number 4  July 2019

agonist at the D2 receptor, has also been investi-
gated in a double blind randomized comparative
trial with perphenazine in individuals with schizo-
phrenia and cocaine dependence. Although aripi-
prazole did not result in significantly lower
proportions of cocaine negative urine tests, a signif-
icant late reduction in craving, 6 weeks after initia-
&
tion of treatment was noted [16 ].
As concerns depot antipsychotics, a secondary
analysis in the PRIDE study compared outcomes
with monthly paliperidone palmitate and oral anti-
psychotics in individuals with schizophrenia with
and without substance use. The depot was associ-
ated with a significantly lower rate of treatment
failure, although this effect was lesser in individuals
&&
with dual diagnosis [17 ]. Paliperidone palmitate
was also associated with fewer all-cause and sub-
stance use related inpatient admissions or long-term
care stays and greater medical cost savings in
another study in veterans with comorbid schizo-
phrenia and substance abuse [18].
With respect to anticraving medications in co-
occurring disorders, the maximum evidence is for
naltrexone, which leads to reductions in drinking
days and number of drinks consumed [19]. The
evidence is limited for disulfiram and is negative
for acamprosate [20].
An analysis of administrative data from a sample
of 8736 adults with SMI, moderate-to-severe opioid
use disorder, and criminal justice involvement
found that individuals receiving opioid dependence
pharmacotherapy (naltrexone, buprenorphine or
methadone) had significant reductions in inpatient
substance abuse treatment, reductions in inpatient
mental health treatment, as well as improved adher-
&
ence to SMI medications [21 ].
A recent double blind, placebo controlled study
comparing glycine and placebo among 20 patients
with schizophrenia/schizoaffective disorder and
alcohol dependence found no significant difference
between the groups for craving, alcohol use out-
comes or improvement in the negative symptoms
of schizophrenia [22]. Similar negative results were
also obtained in seven patients with co-occurring
cannabis use and psychotic disorder treated with
Bedrolite (Bedrocan International, Veendam,
Netherlands) (a form of medical cannabis with
0.4% D9-Tetrahydrocannabinol and 9% Cannabi-
diol). Six of the seven stopped taking Bedrolite
within 1–5 weeks and reported frequent drug seek-
ing behavior as well as restarted cannabis use [23].
BIPOLAR AFFECTIVE DISORDERS
Both mood stabilizers and atypical antipsychotics
[24] have been evaluated in co-occurring substance
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Treatment of substance use disorders Murthy et al.
use and bipolar affective disorders, mainly in comor-
bid alcohol, cannabis and cocaine use disorders [24].
Lithium may not be the treatment of choice in
individuals with bipolar mood disorder and sub-
stance use. Further, a recent study found that comor-
bid alcohol use was associated with partial or no
response to lithium [25]. This is in contrast to early
studies which found lithium useful to promote absti-
nence in individuals with alcohol dependence [26].
Valproate added to lithium was effective in reduc-
ing the number of heavy drinking days compared
with lithium alone in patients with comorbid bipolar
and alcohol use disorders. The numbers of drinks per
drinking day and per heavy drinking day were also
lower in the valproate-treated group after using med-
ication compliance as a covariate. This effect was
related to the serum levels of valproate [27].
Quetiapine, a first-line medication for bipolar
disorder has not been found to be effective in
improving alcohol use outcomes in a large multi-
centric randomized controlled trial [28]. A recent
placebo controlled trial evaluating Quetiapine XR
(AstraZeneca Pharmaceuticals LP, Wilmington, DE)
in patients with bipolar depression and generalized
anxiety with and without alcohol or cannabis use
found that active treatment was better than placebo
in terms of reduction of depressive symptoms.
Decrease in depression scores was greater in the
group with recent alcohol or cannabis use disorder
compared with those without it. However, there
were no significant differences in drinking days/
week or joints of cannabis smoked/week between
the active and placebo groups. This reinforces the
finding that quetiapine in this population may at
best reduce depressive symptomatology but has lit-
tle impact on substance use outcomes [29]. Yet,
quetiapine continues to be widely prescribed for
people with SUD and comorbid mental health dis-
orders. A naturalistic study evaluating the efficacy of
asenapine in 119 psychiatric in patients with bipolar
I disorder with and without SUD showed that
patients improved on disease-related outcomes
(Young Mania Rating Scale (YMRS) and Brief Psychi-
atric Rating Scale) across time points. However, the
improvements in YMRS scores were greater in indi-
viduals without comorbid SUD [30].
Although naltrexone has shown trends toward
reduction in alcohol use in a placebo controlled RCT
&
[31 ], acamprosate was not beneficial and topira-
mate actually led to worse alcohol use related out-
&
comes compared with placebo [31 ].
Other medications like citicoline have been
tested in individuals with bipolar disorder with
comorbid cocaine dependence and found to signifi-
cantly reduce the number of cocaine positive urine
samples compared with placebo in a large outpatient
www.co-psychiatry.com 295
Addictive disorders
double blind RCT [32]. A single arm 12-week prepost
clinical trial in patients with bipolar disorder type II
and comorbid alcohol dependence (n ¼ 45) who were
undergoing regular treatment with valproate and
add-on memantine (5 mg/day) revealed significant
differences in Hamilton Depression Rating Scale
(HDRS), YMRS and alcohol use at follow-up compared
with baseline. However, the lack of a placebo group in
&
this study limit the utility of the findings [33 ].
MAJOR DEPRESSIVE DISORDER
Simultaneous treatment of the mood disorder and
SUD is recommended. Treatment considerations
include interactions between antidepressants and
drugs of abuse as well as the abuse potential of
antidepressants, such as tricyclic antidepressants
(TCAs) [34].
A secondary analysis of adult major depressive
disorder (MDD) outpatients from the Sequenced
Treatment Alternatives to Relieve Depression trial
compared selective serotonin reuptake inhibitor
(SSRI) treatment on quality of life (QOL), functioning
and depressive symptom severity scores between 121
individuals with comorbid MDD and alcohol use
disorders and 2159 individuals with only MDD. Both
groups benefitted from SSRI in terms of depressive
symptoms, although QOL and functioning remained
low in both groups. Alcohol use outcomes were not
reported [35]. A Cochrane review of antidepressants
for treatment of individuals with depression and
alcohol use disorders found that antidepressants
reduced the severity of depression, the number of
drinks per drinking day and increased the number of
individuals abstinent at the end of treatment com-
pared with placebo. Among antidepressants, TCAs
improved rates of response in depression but change
in alcohol-related outcomes was not mentioned.
SSRIs on the other hand improved alcohol-related
outcomes but did not differ from placebo in terms of
&&
depression response [36 ]. A meta-analysis of phar-
macotherapy for the treatment of depression and
anxiety in individuals with opioid dependence on
opioid agonist therapy found that TCAs significantly
improved depression scores, whereas SSRIs were not
different from placebo [37].
Naltrexone, either alone or in combination with
sertraline has been found to be effective in improving
alcohol use outcomes in patients with concurrent
depression [38]. There is accumulating evidence for
the use of buprenorphine as an augmentation strat-
egy in treatment resistant depression [39]. A small
double blind RCT which investigated single high-
dose buprenorphine (32, 64 and 96 mg) in individu-
als with opioid dependence and depression found
significant improvements in depressive symptoms in
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all three groups, but no differences between groups
[40]. A randomized placebo controlled human labo-
ratory trial of a neuroimmune modulator ibudilast in
nontreatment seeking individuals with mild-to-
severe alcohol use disorder found that ibudilast atten-
uated the mood altering properties of alcohol com-
pared with placebo [41]. These offer promising
avenues for further systematic research.
PSYCHOSOCIAL INTERVENTIONS
Psychosocial interventions in individuals with co-
occurring disorders may be delivered in individual
or group formats and often build on established
interventions for SUD such as modified cognitive
behavioral therapy (CBT), that incorporates ele-
ments of relapse prevention and motivational inter-
viewing or integrated group therapy [42].
The interventions are usually provided in the
context of a residential dual diagnosis program, but
can also be delivered in the outpatient setting or in
the community.
An RCT which compared multidimensional
family therapy (MDFT) in the home or community
to residential treatment in 113 adolescents with
substance use and co-occurring mental health issues
found decreases in substance use in both treatment
arms at 2 months. However, 2–18 months after the
baseline, the MDFT group maintained the improve-
ments in substance use as compared with the resi-
dential treatment [43].
Self help groups for this population such as
‘double trouble in recovery’ and other groups based
on 12-step principles have been evaluated [42]. A
recent meta-analysis found a significant and posi-
tive relationship between alcoholics anonymous
attendance and abstinence. The magnitude of ben-
efit did not differ between 6 and 12-month follow-
up or based on the treatment setting (outpatient or
residential) [44].
It is advisable to initiate psychosocial interven-
tions early in the course of treatment even during
detoxification. Early brief psychoeducational group
counseling session linking substance use with mood
and trauma compared with a control cognitive ses-
sion in patients with alcohol use disorders and
comorbid MDD and PTSD was found to improve
motivation for utilizing treatment and decreased
&
readmissions after 6 months [45 ].
A more comprehensive 10-week follow-up psy-
choeducational group therapy intervention, evalu-
ated in a mixed population of individuals with dual
diagnosis (n ¼ 51) found reductions in substance
use, particularly alcohol, among study completers.
However, the dropouts had a significantly greater
proportion of individuals with SMI, whereas the
Volume 32  Number 4  July 2019

completers group had more individuals with neu-
rotic disorders. This suggests that psychoeducation-
based group interventions may not in themselves be
sufficient for individuals with SMI dual diagnosis
[46].
A multicenter, two arm, parallel group, RCT
which assessed the effect of the IMPACT interven-
tion program on changing lifestyle habits in indi-
viduals with psychosis found no significant overall
benefits on physical or mental health subscales of
the short form-36 questionnaire [47]. The NAVI-
GATE program, a coordinated specialty care service
used in the Recovery After Initial Schizophrenia
Episode-Early Treatment Program (RAISE-ETP) study
found no treatment group by time interaction effect
with respect to days of self-reported substance use
over the 2-year follow-up. Further, participant expo-
sure to the substance abuse component of the NAV-
IGATE program was low [48]. These studies suggest
that low intensity psychosocial interventions deliv-
ered by nonspecialists alone may not be sufficient to
improve substance use outcome in patients
with psychosis.
A small pilot study of the ‘HABIT’ program, a 14-
session integrated group therapy intervention con-
sisting of psychoeducation-based cognitive therapy
followed by mindfulness-based relapse prevention
in eight individuals with bipolar disorder and alco-
hol and other SUD found that the intervention is
acceptable and led to decrease in depressive symp-
toms. Half the individuals had reductions in alcohol
and other substance use [49].
There have also been interventions to cope with
illness consequences such as homelessness and vic-
timization. Self-wise, Other-wise, Streetwise training
is a 6-week, 12-session manualized group-based
training focused on enhancing emotion regulation,
conflict resolution and street skills. A multisite sin-
gle-blind parallel randomized controlled trial which
evaluated this intervention in addition to care as
usual (pharmacotherapy combined with individual
and group psychotherapy and/or supportive
counseling), found significant reductions of victim-
ization and violent victimization in the interven-
&&
tion group [50 ].
Technology-based interventions which can
facilitate regular contact with service providers
and address recidivism are being evaluated. A smart-
phone recovery tool developed for individuals with
alcohol use disorders called Addiction-Comprehen-
sive Health Enhancement Support System was
adapted and tested in a Latino population with dual
diagnosis for a period of 4 months post-discharge
from a residential program. The application was
found to have been used actively by 58 out of the
79 (73.4%) users over the course of the study period
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Treatment of substance use disorders Murthy et al.
&
and was deemed to be acceptable by the users [51 ].
The use of supportive text messages for individuals
with alcohol use disorders and depression is also
being explored [52].
SEVERE MENTAL ILLNESS AND NICOTINE
DEPENDENCE
Tobacco-related diseases are a common cause for
mortality in individuals with substance use and
mental health problems [53]. The RAISE-ETP study
found that tobacco smokers with SMI had greater
severity of illness, more missed antipsychotic doses
and poorer QOL compared with nonsmokers [54].
Individuals with SMIs also have lower rates of smok-
ing cessation as compared with other smokers. This
may be related to low rates of delivery of appropriate
pharmacotherapy, such as nicotine replacement
therapy and varenicline. The role of medications
may be more important than behavioral therapy
in this population [55].
A recent study examined sustained abstinence
rates between 12 and 24 weeks in smokers with
schizophrenia and bipolar disorders (SBD) com-
pared with general population smokers. Smokers
who were abstinent following 12 weeks of treatment
with varenicline were randomized to either further
12 weeks of maintenance varenicline or an identical
placebo. In the placebo group, the abstinence rate at
week-24 was lower in those with SBD than for those
without psychiatric illness while in the mainte-
nance pharmacotherapy, there was no effect of
diagnosis on abstinence rates at week-24. The time
to first lapse was also shortest in those with SBD in
the placebo group and longest in those with SBD
who received maintenance varenicline. This indi-
cates the need for maintenance pharmacotherapy in
this population owing to high rates of relapse after
&&
stopping treatment [56 ].
A secondary analysis which evaluated the use of
a combination of varenicline and CBT for 12 weeks
in individuals with schizophrenia and depressive
symptoms with or without a recent suicidal attempt
measured using the Calgary Depression Scale for
Schizophrenia found that depressive symptoms
decreased independent of tobacco abstinence after
&
controlling for baseline depression scale scores [57 ].
This adds to accumulating evidence that neuropsy-
chiatric adverse effects of varenicline may be over-
stated and that its use in individuals with SMI needs
to be encouraged.
Another RCT compared combination extended
treatment (COMB-EXT) (Group CBT, bupropion,
nicotine patch and lozenge) with or without home
visits (biweekly for assessment of second hand
smoke and brief behavioral therapy) to TAU (Group
www.co-psychiatry.com 297
Addictive disorders
CBT and single or combination medications) in
individuals with schizophrenia. It was found that
7-day point prevalence abstinence was significantly
higher in COMB-EXT and home visits group com-
pared with the other two groups [58].
CONCLUSION
Although further clarity is emerging in the manage-
ment of individuals with co-occurring disorders
from different settings, implementation and train-
ing of staff continues to remain a challenge. Studies
indicate that clozapine has an edge over other anti-
psychotics in individuals with schizophrenia and
SUD and this is supported by neurobiological evi-
dence. A typical antipsychotic depot injections such
as paliperidone palmitate show promise. Valproate
is presently the preferred treatment for individuals
with bipolar disorder and SUD and there is accumu-
lating evidence that neither lithium monotherapy
nor quetiapine is efficacious. Naltrexone has been
found to be the most effective anticraving agent for
individuals with co-occurring SUD and schizophre-
nia or bipolar disorders. Opioid replacement
improves both drug use and treatment adherence.
Varenicline shows promise in smokers with schizo-
phrenia and bipolar mood disorders. Psychosocial
interventions also play an important role and
should be initiated early in the course of treatment.
They can be conducted in a nonresidential setting
but should be intensive and draw on established
interventions for treatment of substance use, with
suitable modifications. Further research in the field
needs to focus on interventions in resource poor
settings and technology leveraging to facilitate
more comprehensive evaluation and treatment.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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