Secondary Schizophrenia (57 page)

with psychedelic experiences such as spiritual jour-effects within seconds of IV injection. The plasma half-neys, interaction with famous or fictitious people, and
life of ketamine has been reported to be 1–2 hours
hallucinatory visions. The k-hole ends abruptly but
[49].
When ketamine is used intravenously, duration
can quickly be re-entered with another injection of
of anesthesia is dose dependent and may be as brief as
ketamine.

30 minutes
[50, 51]
with complete recovery taking sev-Because there have been no regionally or temeral hours. Because ketamine does not depress respi-porally circumscribed epidemics of illicit ketamine
ratory or cardiovascular systems, it was widely used
use, it has been difficult to establish the psychiatric
as a field anesthetic by the U.S. army during the Viet-consequences of its abuse. The main evidence for
nam War and continues to be marketed as a valuable
a link between ketamine abuse and psychotic dis-anesthetic for human procedures, especially in chil-order is based on the occasional psychiatric case
dren and in veterinarian practice.

series report
[63, 64];
survey data of ketamine users
Although ketamine anesthesia can produce emer-who reported auditory hallucinations, paranoia, loose
gence phenomena in up to 30% of anesthetized adults,
associations, and unusual thought content among
the symptoms are not as severe as those produced by
the behavioral effects of ketamine
[65];
and psy-PCP
[52].
Emergence symptoms include alterations
chometric data on small groups of ketamine users
in mood state and body image, dissociative and out-

[66, 67, 68, 69].
Chronic ketamine abusers had

of-body experiences, floating sensations, vivid dreams
higher scores on tests of delusional ideation and
Organic Syndromes of Schizophrenia – Section 3

schizotypal symptomatology, which increased with
unteers. In both unmedicated patients and healthy
acute dosing of ketamine
[66, 67, 68, 69],
but also
volunteers, ketamine produced significant increases in
remained elevated at short-term follow-up
[67, 68].

total BPRS scores, reflecting increased thought dis-The very limited literature on the neurocognitive
order and increased negative symptoms (withdrawal-effects of ketamine abuse suggests acute induction of
retardation). Neurocognitive testing showed unmedi-impairments of working, episodic, and semantic mem-cated patients and healthy volunteers both had signif-ory
[68],
and with chronic ketamine use, induction
icant ketamine-induced impairments in verbal recall
of chronic impairments in episodic memory
[69].
In
and recognition memory, patients performing worse
summary, there is evidence of an association between
than healthy volunteers. When rechallenged with
ketamine abuse and increased proneness to quasipsy-ketamine, patients subsequently stabilized on cloza-chotic symptoms and neurocognitive deficits, and psy-pine showed significantly blunted ketamine-induced
chotic disorder resembling schizophrenia; however,
increases in BPRS psychosis ratings
[74].
In summary,
the research supporting these associations is under-unlike PCP the reaction to ketamine was mild and very
developed and does not define the strength of these
brief in medicated patients, and more pronounced
associations.

although still brief in unmedicated patients.

In contrast to patient studies using PCP, experi-Experimental studies of the effects of ketamine
mental use of ketamine in hospitalized patients with
in healthy volunteers confirm that ketamine-induced
chronic schizophrenia is considered ethically accept-neurocognitive deficits show striking resemblance to
able
[70].
This is partly based on experience using
those seen in schizophrenia
[75].
Deficits in episodic
ketamine as an anesthetic for surgery in patients
memory are induced by ketamine consistently in
with schizophrenia stabilized on antipsychotic med-healthy volunteers
[76, 77, 78, 79],
a result not seen
ication, which was associated with only brief mild
with acute amphetamine challenge
[80].
A substan-postperative disturbance and not major psychotic
tial literature indicates selective deficits at the level of
relapse
[71].
Lahti and colleagues
[72]
gave subanes-encoding (or recognition memory) rather than at the
thetic doses of ketamine (0.1, 0.3, and 0.5 mg/kg IV)
level of retrieval
[77, 78, 79, 81, 82, 83, 84],
a selec-to 9 hospitalized patients with schizophrenia stabi-tive effect consistent with differential system dysfunc-lized on haloperidol (0.3 mg/kg/day for at least 12

tion
[85].
Ketamine also induces deficits in working
weeks). Six of the 9 patients were withdrawn from
memory in healthy volunteers
[79, 80, 83,
86, 87],
with
haloperidol for more than 4 weeks before being re-greater impact on manipulation compared with main-challenged with ketamine. In patients on haloperidol,
tenance of information in working memory
[75],
a
ketamine induced 20 minutes postinjection about a 3-distinction reviewed elsewhere
[85].
Deficits in work-fold increase (dose-related) in Brief Psychiatric Rating
ing memory are not observed in acute amphetamine
Scale (BPRS) psychosis scores, which returned to base-challenge
[80].
Ketamine induces deficits in other pre-line within 90 minutes, although 4 out of the 9 patients
frontal functions including: abstraction deficits in rela-reported delayed recurrence of psychotic symptoms
tion to proverb interpretation
[88, 89],
perseverative
for 24 hours after ketamine. In patients off haloperi-errors in sorting tasks
[77,
88, 89],
impaired response
dol, ketamine induced dose-dependent increases in
inhibition
[90]
, and impaired vigilance
[80,
89]
– the
BPRS psychosis scores. Although ketamine-induced
latter not seen with acute amphetamine challenge
[80].

BPRS psychosis scores were slightly higher in patients
Most studies, although not all
[79, 80],
show that
off haloperidol compared with the same patients on
ketamine induces deficits in selective attention
[77,

haloperidol, it was clear that haloperidol provided lit-

78,
88].
Although only some studies report verbal flu-tle protection against the psychotomimetic effects of
ency deficits
[77, 81,
86, 89]
and others do not
[79,

ketamine. Qualitatively, there was remarkable simi-

88],
verbal fluency deficits have been found in chronic
larity between the themes and content of psychotic
ketamine recreational users
[67, 68].
Psychomotor
symptoms induced by ketamine and symptoms asso-speed is also slowed by ketamine
[83,
91].
In sum-ciated with the patients’ schizophrenic illness
[72].

mary, the pattern of neurocognitive deficits induced
In a replication study, Malhotra
et al.
(73] gave
by ketamine resembles that seen in schizophrenia, and
ketamine (0.77 mg/kg IV over one hour) to 13 hos-implicate dysfunction in the same systems affected
pitalized patients with schizophrenia and neurolep-by schizophrenia, namely, the prefrontal cortex and

tic free for at least 2 weeks, and 16 healthy vol-medial temporal lobe.

Chapter 10 – Psychotomimetic effects of PCP, LSD, and Ecstasy

More proximal evidence that ketamine induces
psychotomimetic phenomena at the level of symp-dysfunction in brain systems affected by schizophre-toms, neurocognition, and regional brain activation.

nia has been provided by regional activation stud-It can be concluded therefore, that ketamine challenge
ies in healthy volunteers. Ketamine-induced regional
studies in healthy volunteers have face and construct
brain activation changes have been directly assessed
validity as preclinical models of PCP psychosis, and
using functional Magnetic Resonance Imaging (fMRI)
in turn as models of schizophrenia. Additional sup-to measure the blood oxygen level-dependent (BOLD)
port for PCP-related models may be offered, compar-effect, an index of regional cerebral blood flow
ing them with serotonergic models to examine evi-

(rCBF) change, and Positron Emission Tomography
dence for discriminant validity. This will be sought by
(PET) to measure changes in regional metabolic rate,
reviewing the psychotomimetic effects of the 5HT2A
either in terms of oxygen ([15O]water) or glucose
agonist, LSD, and the indirect serotonergic agonist,
([18F]flurodeoxyglucose: FDG) uptake. As functional
MDMA.

imaging studies of schizophrenia have more often than
not found reduced activation prefrontally
[92, 93, 94],

in the cingulate cortex
[95],
and medial temporal
Lysergic acid diethylamide (LSD)

lobe
[93, 96],
it was predicted that ketamine would
LSD (D-lysergic acid diethyamide) was originally syn-induce decreases in regional brain activation in the
thesized in 1938 but its psychotomimetic effects were
same areas in healthy volunteers. However, contrary
not discovered until 1943 when one of its codiscoverers
to hypothesis, acute ketamine dosing increased acti-experienced “fantastic visions of extraordinary vivid-vation prefrontally
[97, 98, 99, 100, 101, 102, 103],

ness accompanied by a kaleidoscopic play of intense
and in the cingulate cortex
[97, 98, 103]
and thala-coloration” following inadvertent ingestion
[112].
LSD

mus
[97, 102, 103, 104].
No studies reported changes
acts primarily as a functional agonist at the 5HT2A
in the hippocampus or medial temporal lobe. Two
receptor
[113].
LSD quickly distributes to the brain
functional imaging studies of the effects of ketamine
and other body compartments and is metabolized in
in patients with schizophrenia have been reported:
the liver and kidneys. Effects of LSD are felt within
one found ketamine-induced blood flow increases in
an hour after ingestion and can last from 6 to 12

frontal and cingulate regions
[98]
; the other found
hours. LSD is one of the most potent psychotomimetic
ketamine-induced increases in rCBF in anterior cin-drugs known. Oral psychotomimetic dosages are in the
gulate and reduced rCBF in hippocampus
[72].

25–150
µ
g range. Sensory perceptions are altered and
Clinical biomarkers known to be abnormal in

intensified so that colors appear brighter and sounds
schizophrenia have also been assessed in experi-become magnified or perceived as patterns; there is a
mental studies of ketamine in healthy volunteers.

merging of senses (synesthesia) so that sounds become
Contrary to expectation, deficits in prepulse inhibi-whirling patterns of vivid color; perceptions of time
tion (PPI) analogous to those seen in schizophre-and space are distorted, so that seconds may seems
nia have not been observed
[105, 106]
. Indeed, three
like an eternity, and objects become fluid and shift-independent studies showed PPI augmentation after
ing. Depersonalization; experience of feeling merged
ketamine administration to healthy volunteers
[107,

with another object or another person; hallucinations
108, 109].
A single study of schizophrenia-like ocu-and visions; and religious revelations and spiritual
lomotor abnormalities in healthy volunteers admin-insights have been reported
[114, 115, 116].
That is,
istered ketamine showed ketamine-induced smooth
LSD intensifies emotional experience as much as per-pursuit eye-tracking deficits. Ketamine does not sig-ceptual experience
[117].
Physical effects are few and
nificantly reduce P50 suppression
[105, 106].
Deficits
the lethal dose of LSD is so high that it has not been
in MMN analogous to those observed in schizophrenia
estimated. Psychological dependence is very uncom-have been reported in healthy volunteers administered
mon
[118].
Physical dependence does not develop with
ketamine
[110, 111].

LSD
[119]
but if used daily, tolerance to the psy-To conclude, ketamine produces less potent PCP-chotomimetic effects of LSD develops rapidly but dis-like psychotomimetic effects commensurate with its
appears after a few days of abstinence
[114, 115].