Secondary Schizophrenia (46 page)

that play a key role in synaptogenesis and neuri-This hypothesis was tested by Caspi and colleagues
togenesis
[58, 59],
ultimately resulting in enhanced
[67]
in a longitudinal birth cohort study and found
dopamine efflux when exposed to stimulants or stress.

that a functional polymorphism of the catechol-OThe observation that low doses of antipsychotics blunt
methyltransferase (COMT) gene moderated the influ-the behavioral response in sensitized persons
[59]
is in
ence of adolescent cannabis use on adult psychosis:
keeping with this hypothesis.

carriers of the COMT valine-158 allele were more
The concept of sensitization has considerable rel-likely to experience psychotic symptoms after cannabis
evance to the neurobiology of schizophrenia. As has
consumption than carriers of the COMT methion-been noted earlier, stimulants consistently evoke psy-ine allele. In another study, patients with a psychotic
chotic responses in patients with schizophrenia at
disorder and their relatives were exposed to delta-doses that do not provoke such responses in healthy
9-tetrahydrocannabinol in a double-blind placebo-volunteers. This suggests that the brains of schizophre-controlled design. Carriers of the valine-158 allele
nia patients may already be sensitized. Lieberman
were most sensitive to

-9-THC induced psychotic

and colleagues
[60]
suggest that schizophrenic brains
experiences
[68].
Significantly, this finding was condi-seem to have a developmental neural dysregulation.

tional on pre-existing psychosis liability.

This could lead to neurochemical sensitization when
exposed to stress or psychostimulants during adolescence, which in turn leads to psychotic phenomena.

Common neural substrate

Indeed, there is direct evidence of the phenomenon
Although different substances of abuse have differ-of sensitization at a molecular level. Schizophrenia
ent mechanisms of action, a growing body of evi-patients have been shown to have a greater decrement
dence suggests that neuropathological variations of
of D-2 binding by 123I-iodobenzamide, a D-2 radi-certain brain circuits that regulate positive reinforce-oligand, following stimulant exposure than healthy
ment, incentive motivation, behavioral inhibition,
controls, suggesting greater release of dopamine in
executive functions, emotion, and stress may con-these patients
[61].
Similar results have been found
tribute to a common vulnerability to addiction and of
with C-11 raclopride, another D-2 radioligand
[62].

psychosis/schizophrenia (see Chambers
et al.
2001

In this latter study, the effect was observed even in
[69]
for an extensive review).

antipsychotic-na¨ıve patients, suggesting that the effect
The mesolimbic dopamine system [consisting of
was unrelated to antipsychotic activity.

dopamine (DA) neurons in the ventral tegmental area
(VTA) and their target neurons in forebrain regions
such as the nucleus accumbens (NAc)] has been pro-Individual risk factors
posed as a major neural substrate for the reinforc-Among individual risk factors, the effects of a strong
ing effects of natural rewards as well as alcohol and
family history are well documented. Although most
other drugs. All substances of abuse affect this sys-studies have reported the presence of a stronger family
tem
[70]
and this is thought to mediate drug crav-history of schizophrenia among relatives of psychotic
ing. Drug reward and craving is induced by stimuli
substance abusers
[57, 63, 64],
some have failed to find
that facilitate, rather than depress, DA reward systems.

such differences
[50, 53]
Personality difficulties, “psy-Both D1-like and D2-like dopamine receptors mediate
chosis proneness,” and lifetime history of depression
the reinforcing effects of the substances
[71, 72].
Ani-have been associated with patients with SIP
[3,
65]

mals self-administer both D1-and D2-selective ago-in some but not all studies
[50, 53].
One cannot rule
nists. D1, D2, and D3 antagonists all attenuate the
out the confounding effect of interactions among these
rewarding effects of psychostimulant drugs
[73, 74,

118

risk factors. It is conceivable that those with a fam-

75, 76].
The mesolimbic DA system is also implicated
Chapter 8 – Substance-induced psychosis: an overview

in schizophrenia. Several lines of evidence suggest
dala, and the PfC. Neuroimaging and postmortem tis-such a mechanism: (1) all antipsychotic drugs useful
sue studies in schizophrenic patients show abnormali-against positive symptoms of psychosis have dopamine
ties in hippocampal-amygdaloid volume, proportional
receptor D2 blocking properties
[77, 78];
(2) post-to severity of symptoms. These regions normally pro-mortem studies have shown an increase in striatal D2

vide excitatory input to the PfC and frontal subcortical
receptor density but whether this is due to antemortem
structures. It has been hypothesized that developmen-use of D2 blocking agents is debatable; (3) several stud-tal abnormalities in hippocampal and PfC projections
ies show elevated D2 receptor binding in the striatum
to the NAc may contribute to an overall functional
in schizophrenia
[79]
; and (4) abusers of psychostim-hyperresponsiveness to mesoaccumbens DA release
ulants like amphetamines, which enhance dopamine
by reducing cortical and hippocampal regulation over
neurotransmission, experienced delusions, and hallu-DA-mediated responses in schizophrenia.

cinations typical of paranoid schizophrenia.

Recent neuroimaging studies have revealed deficits
There has been much attention on the neural net-in brain volume – hippocampal formation, amygdala,
work implicated in reward, drug addiction, and in
prefrontal cortex, cingulum, and thalamus in alcohol
schizophrenia. Excitatory afferents to the NAc from
na¨ıve offspring of alcoholics who are at higher risk of
the hippocampal formation relay contextual informa-substance use disorders
[80, 81, 82].

tion relevant to reward and motivation. Excitatory
afferents from the PfC relay command and inhibitory
Do drugs cause chronic psychoses or

information to the NAc relevant to regulation of
thought and motivation. In the NAc, glutamatergic
schizophrenia?

afferents from the PfC and the hippocampal formation
In their review of literature on substance-induced
interact with DA afferents from the VTA to regulate
chronic psychoses, Boutros and Bowers
[83]
iden-motivational processes.

tified a subgroup of people with chronic psychoses
In both psychoses/schizophrenia and addiction, a
developing in the context of using commonly abused
functional disorganization of afferent excitatory com-substances. In many cases, they were unable to iden-munication to the NAc contributes to relative hyper-tify any other diatheses/susceptibility factors for psy-responsivity to DA input from the VTA, increasing
choses (e.g., family history, premorbid adjustment dif-motivational salience of drugs and drug-related stim-ficulties) apart from heavy use of substances for long
uli. In schizophrenia, disregulation of hippocampal
periods. On the basis of fairly consistent findings of
outputs may disrupt PfC communication to the NAc,
male predominance, younger age at onset of psychosis,
weakening executive-inhibitory influences by reduc-increased family history of drug use, and better pre-ing the impact of PfC inputs (gating), reducing exci-morbid adjustment, they concluded that SIP disor-tatory drive of PfC-NAc projections, or both. It has
ders have diagnostic validity and there is “presumptive
been suggested that psychotic symptoms emerge from
evidence” regarding the role of substances in causing
a functional hyperactivity of DA neurons projecting to
them.

the NAc, and functional hypoactivity of DA neurons
The issue of cannabis as a cause of schizophrenia
projecting to the frontal cortex. Psychosis and thought
has been researched in greater detail, and many have
disorder may result, in part, from a state of abnormal
reported the temporal association of prior cannabis
glutamatergic cortical activity associated with exagger-use to later development of schizophrenia. Andreasson
ated DA release or dysregulated DA signaling in the
and colleagues linked prior heavy cannabis use to later
NAc. This imbalance may contribute to improper gat-development of schizophrenia in a cohort of Swedish
ing of perceptual and thought processes. The disinhi-conscripts with a long-term (27 years) followup
[84].

bition of subcortical DA systems in schizophrenia par-To rule out the possibility that this association was
allels theories of reduced cortico-striatal tone associ-due to use of cannabis in the prodrome of schizophre-ated with drug addiction. Thus, the evidence of hyper-nia, they studied the association of cannabis use
activity in NAc DA signaling relates both to psychotic
before conscription with development of schizophre-symptoms and addictive behavior.

nia more than 5 years after conscription. The associ-Current theories focus on neurodevelopmental
ation was still significant. Weiser and colleagues
[85]

abnormalities in cortical and temporal-limbic struc-found a similar association between adolescent use of
119

tures, particularly the hippocampal formation, amyg-cannabis and later development of schizophrenia in
Organic Syndromes of Schizophrenia – Section 3

Israeli conscripts. Such an association was found nei-psychotic symptoms (e.g. what substances cause phys-ther for depression nor for drugs other than cannabis.

iological changes resulting in hallucinations or delu-Meta-analytic and systematic reviews
[86, 87]
have
sions); and ii) the ability to differentiate the expected
established a consistent, almost twofold greater risk for
effects of intoxication and withdrawal from psychotic
consequent psychosis among cannabis users. Based on
symptoms. Routine mental status examination should
the criteria of association, temporal priority, and direc-include a thorough description of presenting symp-tion, Witton and colleagues
[88]
opine that cannabis is
toms, description of onset of psychotic symptoms,
a component cause of schizophrenia. Arseneault and
history of current and lifetime substance use, and
colleagues
[86]
calculated that schizophrenia could
a probe of timing and course of the current sub-be averted in about 8% of the population if cannabis
stance use and psychosis. The sources of information
use could be eliminated (population-attributable frac-that the clinician requires to consider are patient self-tion
=
8). The finding that a significant gene X envi-reports, information from family members or other
ronment interaction exists between cannabis use and
reliable informants about patterns of substance use
schizophrenia
[71]
partly explains why not all those
and onset of psychosis, urine toxicology screens if
who use cannabis heavily develop schizophrenia.

available, and observations of clinical staff. The differ-The cumulative evidence from these different lines
ential diagnosis of patients presenting with substance
of research appears to confirm that substances do put a
use and psychosis should include delirium, intoxica-person at risk for developing psychosis. However, var-tion, withdrawal-related psychosis, SIP, and primary
ious susceptibility factors are important in modulat-psychiatric disorders associated with substance abuse.

ing the risk for developing psychosis. This is in keeping with the continuum model of “cocaine psychosis,”

Delirium

hypothesized by Post
[89],
wherein the risk depends
Substance abusers are prone to develop delirium
on interactions between duration and dose of cocaine
due to intoxication or withdrawal of substances
with genetic and experiential predispositions. At the
or associated medical complications, including head
lower end of the continuum of vulnerability to psy-trauma, electrolyte imbalance, hypoglycemia, hepatic
chosis, large doses of substances abused for long peri-encephalopathy, infections including meningitis, sep-ods would cause psychosis (substance is both neces-ticemia, and so on. Delirium should be suspected when
sary and sufficient to cause psychosis). In the middle
there is acute onset of psychosis, fluctuating conscious-of the continuum are conditions, where substances are
ness, marked inattention, disorientation (particularly
necessary, but not sufficient cause for psychosis. At the
to time), visual hallucinations and illusions, signs of
other end, psychosis may develop following little or
autonomic arousal, affective dysregulation (commonly
no exposure to drugs (substance use is not a neces-fear, but may include euphoria or apathy), and abnor-sary cause; may be coincidental). In the latter condi-mal motor behavior (commonly restlessness, but may
tion, there is consistent evidence that substance use
include retardation or catatonic posturing). Detailed
brings down the age of onset
[90, 91]
– one of the rea-neurological examination and appropriate investiga-sons for earlier age of onset of schizophrenia in males
tions lead to accurate diagnosis, which can be life
is greater prevalence of substance use in them. Con-saving.