Secondary Schizophrenia (52 page)

group also investigated the auditory ERPs during a
In the absence of long-term follow up of large
dichotic syllable discrimination task in 16 unmedi-cohorts of patients with cocaine-induced psychosis,
cated subjects in residual states following the remis-it is not known whether these differences from idio-sion of MA-induced paranoid-hallucinatory states
132

pathic schizophrenia would persist. Of interest is the
[55]
. Extrapolation from these findings suggests some
Chapter 9 – Stimulants and psychosis

similarity in susceptibility to paranoid-hallucinatory
between drug-induced and idiopathic schizophrenia
states between MAP and schizophrenia.

[62].
On the other hand, the few functional imaging
In a separate line of investigations, evoked res-studies examining the effects of prolonged or repeated
ponses were used to examine the inhibitory function
psychostimulant use or administration focused on
of the brain when repetitive identical stimuli are pre-probing the mechanisms underlying the sensitization
sented, that is, habituation and sensory gating. Most
of the effects of these chemicals on the brain. These
notably, a deficit in inhibiting irrelevant incoming
studies are discussed in subsection Mechanisms.

sensory input was observed in abstinent cocaine-dependent individuals
[56].
The finding was later replicated in a more racially mixed group
[57].
More
Mechanisms

recently, our group provided further evidence of a
Among a number of proposed mechanisms by which
deleterious effect of chronic cocaine on gating of the
repeated use or administration of psychostimulants
P50 evoked response
[23].

could result in a longer lasting increase in the suscep-Transcranial magnetic stimulation (TMS) was also
tibility to psychosis, sensitization holds a prominent
used to examine cortical inhibition and excitability in
position.

this group of abstinent cocaine-dependent individuals.

Repeated treatment with psychostimulants pro-The initial TMS studies provided evidence of increased
duces changes in both brain and behavior that far out-cortical inhibition
[58].
This finding was replicated in
last their initial pharmacological actions
[63].
Explo-a larger sample and was interpreted as a compensatory
ration of sensitization mechanisms and effects of
protective mechanism against the epileptogenic prop-repeated exposure to psychostimulants in animals has
erties of cocaine
[59].

been extensive. Discussion of this extensive literature
Electrophysiological studies in cocaine-dependent
is beyond the scope of this chapter, however the inter-individuals suggest a complex mechanism for the
ested reader is referred to a number of authoritative
development of psychosis in these subjects. Deficits
reviews
[64, 65, 66, 67].
It is interesting to note that
in the inhibition of incoming irrelevant sensory input
the changes observed with chronic amphetamine and
(i.e. sensory gating) have been repeatedly demon-cocaine administration in rats, although similar, are
strated in schizophrenia patients
[60].
As mentioned
not identical, possibly contributing to the differences
earlier, a similar decrease in inhibitory capacity was
in clinical effects of the two drugs.

demonstrated in abstinent cocaine users
[23,
56].

Lieberman and colleagues
[1]
suggested that the
This decreased inhibition was correlated with psy-initial aggravating event by which stimulant abuse
chosis proneness in this population
[23].
The find-could produce a chronic schizophrenic syndrome
ings of increased inhibition demonstrated via TMS

is enhanced dopaminergic activity that manifests as
and decreased inhibition demonstrated via evoked
positive schizophrenic symptoms. Continued pro-responses presented a dilemma for interpretation. A
longed excessive dopaminergic activation is believed
recent study utilizing additional TMS-based measures
to induce neuronal degeneration in dopamine systems,
of cortical excitability, namely paired-stimulus facilita-leading to a hypodopaminergic state and negative
tion and inhibition, provided evidence consistent with
symptoms
[2].
In fact, chronic amphetamine treatment
increased excitability or decreased inhibition
[61].

in rats is well documented to be toxic to dopamine
Given that the paired-stimulus TMS technique has
nerve terminals
[55].
Yui and colleagues
[2]
specu-been rather strongly linked with cortical inhibitory-lated that a reduction in dopamine could result in post-excitatory mechanisms, and that it is likely that sen-synaptic receptor supersensitivity, helping to explain
sory gating may be strongly influenced by subcortical
the re-emergence of positive symptoms after tran-mechanisms, we postulate that some form of a cortical-siently increased dopamine availability, as has been
subcortical imbalance in the excitatory-inhibitory bal-observed during stress or exposure to dopaminergic
ance may be important for the development of psy-drugs.

chotic symptoms in cocaine users.

Evidence for sensitization in humans is found
Finally, structural imaging studies compar-

in a small number of studies
[68, 69].
Strakowski
ing groups of idiopathic and presumably chronic
and colleagues
[68]
demonstrated that when two
psychostimulant-induced psychotic patients are virtu-doses of a stimulant were given to volunteers free
133

ally nonexistent. One CT study found no differences
from psychosis, the second dose produced a greater
Organic Syndromes of Schizophrenia – Section 3

“sensitized” response. Stimulant users studied by
behaviors, psychotic state, and relapse. These
Brady and colleagues
[70]
reported psychotic symp-researchers concluded that sensitisation phenomena
toms occurring with lower doses over time. Yui and
to the drugs or endogenous dopamine should be
colleagues
[29]
concluded that the development of
involved in the mechanisms underlying the develop-MAP may therefore be related to persisting brain
ment of such susceptibility. Consequently, common
damage or changes in brain metabolism induced by
molecular mechanisms of sensitization phenomena
repeated MA use, and studies of the clinical course
may develop in the three conditions they studied.

and neurological basis of MAP psychosis may provide
Laruelle
[72]
described the role of endogenous sen-insights into the pathophysiology of schizophrenia.

sitization in the pathophysiology of schizophrenia in a
Boileau and colleagues
[71]
investigated sensi-review of brain imaging studies. He observed that sen-tization to stimulants in humans with an [11C]

sitization of mesolimbic dopamine systems had been
raclopride/Positron Emission Tomography (PET)
postulated by several authors to underlie the develop-study to determine whether behavioral and neuro-ment of dopaminergic abnormalities associated with
chemical sensitization occur in healthy individuals
schizophrenia. Laruelle noted that results of recent
after limited exposure to amphetamine in a laboratory
brain imaging studies indicated that schizophrenia
setting. These researchers conducted an open-label,
was associated with increased amphetamine-induced
1-year follow-up of repeated amphetamine admin-dopamine release, and that this exaggerated response
istration in healthy volunteers. Ten healthy men
was detected in patients experiencing an episode
(mean
±
SD age, 25.8
±
1.8 years) were administered
of clinical deterioration but not in clinically sta-3 single doses of amphetamine (dextroamphetamine
ble patients. Laruelle asserted that because increased
sulfate, 0.3 mg/kg by mouth) on 3 separate days. Using,
stimulant-induced dopamine release was a hallmark
positron emission tomography (PET) and [11C] raclo-of sensitization, these results supported the view
pride, these researchers measured dopamine release
that schizophrenia was associated with a process of
in response to amphetamine on the first exposure
endogenous sensitization. He further postulated that
(day 1) and 14 days, and 1 year after the third expo-amphetamine-induced hyperactivity of the dopamin-sure. Boileau and colleagues reported that the initial
ergic system sustained over a certain period of time is
dose of amphetamine caused dopamine release in
in itself sufficient to induce a psychotic state in other-the ventral striatum (a reduction in [11C] raclopride
wise healthy humans, although the role of an underly-binding). The authors concluded that, “consistent
ing vulnerability to this effect cannot be entirely ruled
with a sensitisation-like phenomenon, on 14 and
out. Based on the preclinical evidence that dopamine
365 days after the third dose of amphetamine there
projection to the prefrontal cortex acts as a buffer that
was a greater psychomotor response and increased
opposes the development of sensitization in subcorti-dopamine release (a greater reduction in [11C]

cal dopamine projections, Laruelle proposed that, in
raclopride binding), relative to the initial dose, in
schizophrenia, neurodevelopmental abnormalities of
the ventral striatum, progressively extending to the
prefrontal dopaminergic systems might result in a state
dorsal caudate and putamen.” The authors also noted
of enhanced vulnerability to sensitization during late
that proneness to sensitization was predicted by a
adolescence and early adulthood. It is also proposed
high novelty-seeking personality trait and self-rating
that D2 receptor blockade, if sustained, might allow for
assessments indicating impulsivity. Boileau and
an extinction of this sensitization process, with pos-colleagues concluded that sensitization to stimulants
sible re-emergence upon treatment discontinuation.

can be achieved in healthy men in the laboratory, and
Laruelle concluded that a better understanding of the
that this phenomenon is associated with increased
neurocircuitry associated with endogenous sensitiza-dopamine release and persists for at least 1 year.

tion and its consequence in schizophrenia might be
The role of sensitization was also examined by
important for the development of better treatment and
Ujike and colleagues
[3]
. They found that three differ-relapse prevention strategies.

ent conditions – psychostimulant-induced behavioral
Finally, aside from genes and psychostimulants,
sensitization in rodents, psychostimulant-induced
there are other factors that are associated with psy-psychoses in human, and chronic schizophrenia –
chosis or schizophrenia, such as prenatal influenza
demonstrated similar longitudinal alternations, pro-

[73],
prenatal drug treatment (e.g. reserpine), and
134

gressively enhanced susceptibility to abnormal
obstetrical complications
[74],
most of which are
Chapter 9 – Stimulants and psychosis

known to induce dopamine supersensitivity and eleas schizophrenia
[18].
The current trend is for ini-vated D2High receptors
[73].

tial treatment with antipsychotics, with a bias toward
Although clear and persisting neurotoxicity to
the atypical antipsychotics as first-line treatment. To
dopaminergic projection fields can be produced by
date, there has been no evidence that typical antipsy-continuous amphetamine or methamphetamine use,
chotics have efficacy in decreasing craving among
continuous cocaine administration apparently does
substance abusing psychotic patients. Evidence for
not induce a similar neurotoxicity and this makes
atypical antipsychotic use suggests some measure of
DA neurotoxicity a poor candidate for an underpin-efficacy, but remains limited to case reports and small
ning of stimulant psychoses. However, both contin-open-label patient series. The length of appropriate
uous amphetamine and cocaine exposure induce a
pharmacological intervention is unknown and no con-strong pattern of degeneration that is confined to
sistent guidelines exist in the literature. Barr and col-the lateral habenula and its principal output pathway,
leagues reported a small case series that indicated that
fasciculus retroflexus
[75].
This finding has led to a
antipsychotic treatment beyond the acute psychotic
reconsideration of the role of these structures in psy-episode may protect against future psychotic episodes,
choses. The habenula, as the chief relay nucleus of the
even at very low doses
[18].