Secondary Schizophrenia (58 page)

more than 30-fold lower NMDA receptor complex
No epidemiological study has determined the rela-binding activity
[57]
compared with PCP. Qualita-tionship between LSD use and the incidence of psy-

tively, however, the two analogues induce equivalent
chotic disorder. Initially, LSD was considered to have
Organic Syndromes of Schizophrenia – Section 3

therapeutic value and reviews of its use with psychi-in the incidence of psychotic disorder. In fact, only
atric supervision concluded that prolonged psychosis
a total of 75 individual case reports of putative LSD

following LSD was rare
[120, 121].
LSD therapy was
psychosis were found in a recent worldwide review
initially applied to patients with an established his-

[127].
The occurrence of psychosis in the setting of
tory of schizophrenia with only a small risk of causing
LSD abuse appears to be more related to individual
relapse
[122, 123].
However, following broader illicit
vulnerabilities than specific drug actions. This does not
use of LSD in the late 1960s, a number of case series
mean that adverse events with LSD do not occur
[125].

reports of psychosis in patients using LSD were pub-Acute LSD intoxication is associated with panic attacks
lished (see [124, 125] for reviews). Patients with psy-and harm from misadventure, and a long-term conse-chotic disorder who had used LSD were said to present
quence, Hallucinogen Persisting Perception Disorder
with phenomenologically similar symptoms and out-

(HPPD) or “flashbacks,” has diagnostic validity
[141].

come to those with schizophrenia who did not take
Nonetheless, models based on LSD-related drugs are
LSD
[126, 127, 128, 129, 130, 131].
However, in con-not irrelevant to the study of schizophrenia, especially
trast to many patients with PCP-induced psychosis,
to investigate disturbances in serotonergic regulation
most individuals presenting with psychosis in the set-

[142, 143],
because of the 5HT2A receptor antagonist
ting of LSD abuse showed poor premorbid adjustment,
actions of atypical antipsychotics
[136,
144, 145],
and
associated with prior psychiatric admissions
[126, 127,

the potential relevance of interactions between gluta-

128, 129, 130, 131]
or family history of psychotic or
matergic and serotonergic systems in the pathogenesis
other serious psychiatric illness
[130, 132].
Contem-of schizophrenia
[113,
140, 146, 147, 148, 149].
For the
porary clinicians could not determine whether psy-purposes of this review, however, at this stage we con-chosis in the setting of LSD abuse was a separate
clude our formal consideration of LSD-induced psy-diagnostic entity or simply represented a subgroup of
chotomimetic effects as a model of schizophrenia.

patients with schizophrenia who used LSD. An important area of agreement in the clinical literature was
the view that the symptoms of acute LSD intoxication
Ecstasy

were phenomenologically different to the symptoms
MDMA (3,4-methylenedioxy-methamphetamine) is
of schizophrenia
[133, 134, 135, 136].
LSD-induced
a ring-substituted amphetamine derivative. It was
perceptual disorders are visual rather than auditory;
patented in 1914 but never made commercially avail-the visual distortions are not frank hallucinations but
able. MDMA was classified a restricted drug in the
have the character of illusions; delusional ideation is
United Kingdom in 1977 and in the United States
not stable and usually insight is retained; negative
in 1985. MDMA is almost always consumed orally,
symptoms are at most mild; and LSD-induced phe-the psychoactive dose being about 100 mg. The pri-nomenology is often distinguishable by patients with
mary effect of MDMA is to produce a positive mood
schizophrenia from their primary symptoms (
[133,

state with feelings of euphoria, intimacy, and close-

134, 135, 136].
In marked contrast to both schizophre-ness to other people, an effect that distinguishes it from
nia and PCP psychosis, the hallucinogenic effects of
amphetamine or hallucinogens
[150].
MDMA also has
acute LSD intoxication subside rapidly with benzodi-stimulant effects as well as mild psychedelic effects on
azepines
[16]
unless delirium is evident. Other dis-insight and perceptual and sensual enhancement. The
similarities with schizophrenia were reported in LSD-peak psychoactive effects last on average 4–6 hours,
related (N,N-dimethyltryptamine [DMT] or psilocy-although the half-life of MDMA is approximately 9

bin) challenge studies in healthy volunteers measuring
hours in humans
[151].
Tolerance to the psychoactive
PPI
[107,
137]
or MMN
[138,
139]
that did not find
effects develops rapidly
[153].
No physical withdrawal
deficits, although deficits in attention
[140]
and P50

syndrome has been described
[153],
but psychologi-suppression
[137]
with DMT were reported.

cal dependence is common
[118].
Illicit Ecstasy tablets
In conclusion, although LSD has obvious hallu-often contain compounds related to MDMA, such as
cinogenic effects, it is debatable whether it should
MDE (3,4-methylenedioxy-methamphetamine). The
be considered psychotogenic. Despite periods of rel-generic term ‘“Ecstasy” is now preferred because it may
atively high and low rates of use of LSD in communi-refer to MDMA, analogues of MDMA, or combination
ties, no formal or informal epidemiological data have
of these
[154].
Ecstasy use by young people has world-

linked fluctuations in community use to variations
wide popularity
([155, 156].
In the United Kingdom
Chapter 10 – Psychotomimetic effects of PCP, LSD, and Ecstasy

during the mid-1980s, all-night dance parties called
exposure; and polysubstance abuse) rather than drug
‘“raves” became popular. The drug of choice for people
related. Soar and colleagues
[172]
reviewed published
attending raves was Ecstasy and the popularity of this
psychiatric case studies from the previous 10 years
youth culture resulted in an explosion in recreational
involving MDMA. Of the 38 cases, 22 had a psy-use. Among US college students there was a steady
chotic disorder or symptoms. Two of this subgroup
increase in Ecstasy use from 2.0% in 1991 to 13.1% in
had a family history of psychosis, an observed rate
2000
[157].
Similarly, in the Australian general popu-that is precisely comparable to the expected rate with
lation, there is a steady increase in the proportion of
schizophrenia itself. In addition, in the psychotic
people who have ever tried Ecstasy from 4.8% in 1998,
patients confounding arose from greater Ecstasy use
6.1% in 2001, to 7.5% in 2004
[158, 159].
Amongst
being associated with heavier polysubstance use. In
dance or rave party attendees, the use of Ecstasy is far
an Italian series
[173]
of 32 cases of psychotic disor-more common (up to 80% prevalence) than the use of
der in Ecstasy users (patients with self-reported poly-ketamine and PCP
[160, 161, 162];
however, polysub-substance abuse excluded), symptomatology was not
stance abuse (especially methamphetamine, cannabis,
phenomenologically distinctive, and many cases had a
and hallucinogens) among Ecstasy users is the norm
family history of psychiatric disorder or past personal
[62].

history of nonpsychotic psychiatric disorder, making
Public alarm concerning the dangers of Ecstasy use
it impossible to determine whether or not Ecstasy was
initially arose from reports of sudden death in young
the primary cause of psychosis. In a community sam-healthy users, especially when ingestion occurred at
ple, the occurrence of schizophrenia was not related
dance parties that were typically hot, crowded, venues
to heavy Ecstasy exposure
[170].
There is only a sin-with loud repetitive music and light shows
[163, 164].

gle case report in which experimental MDMA intox-Cause of death was either cardiac arrhythmia or malig-ication produced an acute toxic hallucinosis lasting
nant hyperthermia, and usually related to polysub-2.5 hours
[174],
emphasising the rarity and idiosyn-stance ingestion
[165].
However, a direct link between
cratic nature of this adverse event. The lack of evi-the fatalities and Ecstasy use is supported by a strong
dence of an association between psychotic disorder
correlation between rates of Ecstasy use and rates of
and Ecstasy use described earlier has not prevented the
fatalities
[166].
Milder effects of intoxication include
medical opinion that Ecstasy “has a special risk for per-nausea, loss of appetite, tachycardia, hypertension, jaw
sistent organic psychoses” from being published
[175].

tension, bruxism, and sweating
[167].
Chronic adverse
Clinical biomarker studies have not supported MDMA
events associated with Ecstasy use include extensive
challenge as a model of schizophrenia. Unexpected
polydrug use, high rates of intravenous drug use, and
increases (i.e. not deficits) in PPI have been observed
financial, relationship, and occupational problems
after administration of MDMA in healthy volunteers
[168].

[176, 177]
and in chronic Ecstasy abusers
[178].
There-Although there are many studies reporting an
fore, for the purposes of this review, MDMA-induced
association between Ecstasy use and mental disor-psychotomimetic effects do not emerge as a model of
der, especially depression and anxiety, it is impossi-schizophrenia.

ble to determine in cross-sectional studies whether
this relationship is due to Ecstasy, associated polysubstance abuse
[155]
, or whether it pre-or postdates
Animal studies

Ecstasy use. In prospective
[169]
or retrospective
[170]

This subsection reviews animal models induced by
comparisons of the age-of-onset of mental disorder
PCP and analogues to further assess the construct and
and age-of-onset of Ecstasy use, psychiatric disorder
predictive validity of the PCP model of schizophrenia.

appeared to precede Ecstasy consumption. A meta-We examine how closely these animal models replicate
analysis showed that the strength of the association
pathophysiological and theoretical processes hypoth-between Ecstasy use and depressive symptomatology
esized to underlie schizophrenia. Evidence of predic-was weak and unlikely to be clinically relevant
[171].

tive validity is presented by comparing the potency
Psychotic disorder as an adverse reaction to Ecstasy
of novel compounds in reversing PCP-related psy-use appears to be rare and idiosyncratic, mainly deter-chotomimetic effects in the model with their antipsy-mined by user-related variables (familial predispo-chotic effect in patients with schizophrenia. First, prin-

sition; previous psychotic episodes; very high dose
ciples and constraints concerning disease modeling in
Organic Syndromes of Schizophrenia – Section 3

animals are noted and illustrated by considering the
theoretical process, “sensorimotor gating”
[45]),
that
amphetamine-induced model of psychosis.

has an equivalent measureable in the animal model
(“homologous” measurement). However, the disease
nonspecificity of PPI and hyperlocomotion constrains
Animal modeling: principles and constraints

their utility in animal studies of the pathophysiology of
Attempts at modeling psychiatric diseases in their
schizophrenia.

entirety are futile because rodents have much sim-This constraint has been addressed in ampheta-pler brain structure than humans, making it impos-mine-induced animal models by measuring brain
sible for rodents to display the same kinds of
system/neuronal dysfunction, in addition to assess-complex symptoms as humans. It is therefore unre-ing behavioral change. A step in this direction was
alistic to expect homology on all aspects of a disor-based on findings in rodents and primates that
der across two species
[179].
A more feasible approach
induction of hyperlocomotion by dopamine agonist
is to model specific signs or symptoms of the dis-

(e.g., amphetamine) is related to increased subcortical
ease, or neurobiological correlates, for which there
dopamine release in ventral striatum
[183].
Notably,
are relatively equivalent behaviors or measures in
these preclinical findings informed research that pro-both humans and rodents. This approach is illustrated
duced the first direct evidence in living patients of sig-by the dominant animal model for schizophrenia,
nificant dysregulation of subcortical dopamine neuro-amphetamine-induced hyperlocomotion in rodents, a
transmission in schizophrenia using an in vivo recep-model that currently serves as the ‘“gold standard” in
tor binding method, a consistently confirmed finding
evaluating other models, especially the PCP model.