STRUCTURAL AND METABOLIC DIFFERENTIATION

BETWEEN BIPOLAR DISORDER WITH PSYCHOSIS AND

SUBSTANCE-INDUCED PSYCHOSIS: AN INTEGRATED
MRI/PET STUDY
 Substance Abuse in mental illness
National Co-morbidity Survey (NCS)
• Nearly half of individuals with a past year
substance use disorder also had a mental disorder

• Mental disorders found to be most prevalent

included affective disorders, anxiety disorders,
personality disorders, and psychotic disorders

To make the situation more complicated, the co-

occurring disorders also affect each other and
interact
 Why is it important to study
substance abuse in Mental illness?

• Poor adherence
• Poor outcome
• Higher rate of hospitalisation
• Higher rate of criminal behaviours
• Worse treatment course
• More mood changes
• More psychotic symptoms
What comes first: Substance abuse or
the mental health problem?
• Drugs are often used to self-medicate the
symptoms of depression or anxiety.

• Drug abuse can make symptoms of a mental

health problem worse.

• Drug abuse can increase underlying risk

for mental disorders.
 Why Do Drug Abuse and Mental
Disorders Commonly Co-occur?

• Overlapping genetic vulnerabilities

• Overlapping environmental triggers

• Involvement of similar brain regions

Because of this overlap, drugs of abuse

can cause symptoms that mimic
most forms of mental illness
Lifetime Prevalence of Drug Disorders Among
Persons With Various Mental Disorders
(vs. any Drug Disorder Alone)

Regier DA et al., JAMA 1990

Conway et al. J Clinic Psychiatry 2006
 Bipolar Disorder and substance abuse
During the past 20 years, there has been increased awareness
that substance abuse is overrepresented in individuals with
bipolar disorder.

Co-morbidity with Substance Abuse – Ranging from 32% to 38%

(Toftdah et al., 2016; Grant et al., 2005).
Nonetheless….

Relatively little has been written about the

neurobiological differences between bipolar
disorder with co-occurrent substance abuse and
substance-induced psychotic disorder
Toftdah et al. 2016
 Purpose of the study
To investigate gray matter volumes and brain
metabolism in psychotic BD patients with and without
substance abuse and in patients with substance-
induced psychosis coupling Magnetic Resonance
Imaging and Positron Emission Tomography.
 Hypothesis
• Chronic use of drugs may alter the way the brain
functions and therefore we hypothesized that
substance abuse may have direct effects on brain
regions underpinning the pathophysiology of BD
patients
 Participants and Methods
All Patients employed in this study have been recruited at the
Psychiatric Clinic, Fondazione IRCCS Ca’ Granda, Ospedale
Maggiore Policlinico, University of Milan, Milano, University of
Milan (Director: Prof. Carlo A. Altamura)

- 13 BD patients with substance abuse

- 20 BD patients without substance abuse
- 16 Substance-Induced Psychotic patients
- 27 Healthy Controls for MRI analysis
- 27 Healthy Controls for PET analysis

3T MRI and a 18-F-FDG-PET scanning in

resting condition.
Magnetic Resonance Imaging
High spatial resolution 
high definition of brain
structures

Low temporal resolution [s]

Positron Emission Tomography

Able to detect disease before
changes in the anatomy by
studying brain function through
biochemical functions
Low spatial resolution
PET scan risks caused by the
radioactive component used
during this procedure
Original T1 image Segment images (GM, WM & CSF) Normalise GM seg. to template
& remove extra-cerebral voxels to obtain norm. parameters

Pre-processing of Voxel-Based Morphemetry Approach

Smooth final images Apply norm. parameters to

original images
 Pre-processing of PET Approach

Original PET image Coregistered GM seg. to T1 images Smooth final images

to obtain norm. parameters
 Statistical analyses
- The same statistical analyses (ANCOVA) were performed
for both the MRI and PET approaches with age, sex and
intracranial volumes as covariates.

- Post-hoc analyses were performed to detect gray matter

volumes and brain metabolism abnormalities between
the four groups.
Structural MRI Results
Analysis of Covariance between the four
groups
 Brain region BA Laterality
Superior Frontal 47 Right
Superior Frontal 6 Left
Superior Frontal 9 Left
Superior Frontal 8 Left
Superior Frontal 10 Right
Superior Frontal 9 Right
Middle Frontal 46 Right
Precentral 6 Right
Superior Temporal 38 Right
Superior Temporal 38 Left
Putamen - Right
P <0.05 Family-Wise Error corrected
Post-hoc analyses
 Brain region BA Laterality
BD patients without substance abuse <
Healthy Controls
Superior Frontal 9 Right
Superior Frontal 9 Left
Superior Frontal 10 Left
Superior Frontal 8 Left
Superior Frontal 8 Right
Superior Temporal 21 Left

Brain region BA Laterality

Substance-Induced Psychosis < Healthy
Controls
Superior Frontal 47 Right
Middle Frontal 9 Right
Precentral 6 Right
Precentral 4 Left
Superior Temporal 20 Left
Putamen - Right

Brain region BA Laterality

BD patients with substance abuse < Healthy
Controls
Inferior Frontal 47 Right

( all P <0.05 Family-Wise Error corrected

 Brain region BA Laterality

Substance-Induced Psychosis < BD patients

with substance abuse
Superior Frontal 10 Right
Superior Frontal 10 Left
Superior Temporal 38 Right
Middle Temporal 21 Right

Brain region BA Laterality

Substance-Induced Psychosis < BD patients
without substance abuse
Superior Frontal 10 Right
Superior Frontal 6 Left
Superior Frontal 11 Left
Superior Temporal 38 Right
Superior Temporal 38 Left
Inferior Temporal 20 Left

all P <0.05 Family-Wise Error corrected

PET Results
Analysis of Covariance between the four groups
 Brain region BA Laterality
Precentral 44 Left
Inferior Frontal 9 Left
Precentral 6 Left
Postcentral 3 Right
Middle Temporal 37 Right
Superior Temporal 41 Right
Superior Temporal 22 Right
Superior Temporal 42 Left
Superior Temporal 41 Left
Superior Temporal 38 Right
Inferior Temporal 37 Left
P<0.005 uncorrected
Post-hoc analyses
 Brain region BA Laterality
BD patients without substance abuse < Healthy Controls
Precentral 9 Left
Inferior Frontal 46 Left
Inferior Frontal 47 Left
Precentral 44 Left
Middle Temporal 21 Left
Superior Temporal 41 Left
Middle Temporal 37 Right

Substance-Induced Psychosis < Healthy Controls

Inferior Frontal 9 Left
Middle Frontal 10 Left
Superior Temporal 42 Left
Superior Temporal 13 Right
Inferior Temporal 20 Right
Middle Temporal 21 Right

Substance-Induced Psychosis > Healthy Controls

Putamen - Right
Putamen - Left
Caudate - Right

BD with substance abuse < Healthy Controls

Medial Frontal 10 Left
Inferior Frontal 9 Left
Superior Temporal 42 Left
Inferior Temporal 20 Right
Superior Temporal 13 Right
Middle Temporal 21 Right

all P<0.005 uncorrected

Brain region BA Laterality
Substance-Induced Psychosis > BD
patients with substance abuse
Superior Frontal 10 Left
Precentral 6 Right

Brain region BA Laterality

Substance-Induced Psychosis < BD
patients without substance abuse
Superior Frontal 10 Right
Superior Temporal 22 Right
Superior Temporal 41 Left

all P<0.005 uncorrected

 Conclusion (I)
• To the best of our knowledge, this is the first study trying to integrate
metabolic and morphological data to study the interplay between
psychosis and substance abuse in BD.

• This study stems from the interest of our group in exploring brain
metabolic changes in Bipolar Disorder, Schizophrenia and Substance-
induced psychosis (Altamura et al., 2013; Dragogna et al., 2014).
 Conclusion (II)
• Regardless of the presence of substance abuse, BD patients showed extensive
structural and metabolic fronto-temporal alterations compared to healthy
controls in brain regions well-known to be involved in this disorder, including
dorso- and ventro-lateral prefrontal cortices as well as superior , middle and
inferior temporal gyri (Brambilla et al., 2005; Selvaraj et al., 2012).

• Therefore, these findings further support the pivotal role of these structures
in the pathogenesis of BD which might, in turn, play a role in the genesis of
mood regulation and neurocognitive deficits observed in these patients.
 Conclusion (III)
• Substance-induced psychotic patients showed similar but more
extensive structural and metabolic alterations in fronto-temporal
regions, including dorso- and ventro-lateral prefrontal cortex as well as
superior and middle temporal regions compared to healthy controls
and BD patients with or without substance abuse.

• These results are in keeping with previous evidence reporting

significant prefrontal reductions in GM volumes (Bartzokis et al., 2000;
Makris et al., 2008a) and density (Dalwani et al., 2011) in drug addicts.

• These fronto-temporal alterations might be in line with what have

been reported in recent years by MRI studies in schizophrenia
(Buchanan et al.,2004; Zhang et al., 2015). Indeed it has been
hypothesised that substance-induced psychosis might lie within a
"grey" overlapping zone between schizophrenia or BD within a
psychosis continuum (Keshavan et al., 2011; Altamura and Goikolea,
2008).
 Conclusion (IV)
• Finally, our investigation reported direct and unique structural and
metabolic disruptive effects of substance abuse on striatal regions
(putamen and caudate) in substance-induced psychotic patients compared
to healthy controls.

• These structures are implicated in the reward processing and they have
been reported to play a crucial role in the neurobiology of drug addiction
(Kobza et al., 2015).

• Indeed, previous studies underlined that a dysfunction in reward system

may lead to excessive sensitivity to reward or a failure of inhibition, and
these alteration seem to be at the base of increased risk of substance abuse
(Hommer et al., 2011; Probst et al., 2013).

• Moreover, it has been shown that an alteration in the reward processes may
lead to higher risk of developing substance abuse (Garner et al., 2009).
Future directions
Increase
sample size
Include a control
group
Divide patients
according to the
drug used
Explore the
combine effect of
specific genetic
variants on brain
volumes
Thank you for your attention