Secondary Schizophrenia (140 page)

disorders mentioned above. This may suggest an asso-a. Huntington’s Disease (HD)
CAG

ciated genetic abnormality that predisposes the indi-b. Dentatorubral-Pallidoluysian atrophy
CAG

viduals to psychosis, or perhaps some other vulnerabil-

(DRPLA)

ity factor that may be epigenetic or environmental. It
c. Spinocerebellar ataxia, types 1, 2, 3, 6, 7, 17

CAG

could also mean that the nature of the disorder in these
individuals is such that they develop a vulnerability to
d. Kennedy’s Disease

CAG

(x-linked spinal and bulbar muscular

psychosis owing to it. The investigation of these factors
atrophy)

could result in important insights into the pathogene-

II. Untranslated triplet repeat disorders

sis of schizophrenia.

a. Spinocerebellar ataxia

CIG

type 8

CAG

Pathology

type 12

If the neuropathology of HD creates a vulnerability
b. Friedreich’s ataxia (FRDA)

GAA

for SLP, it would be useful to examine this to under-c. Mytomic dystrophy
∗

CIG

stand the nature of pathology that might underlie psy-d. Fragile X syndrome
∗

CGG

chosis. In particular, the early changes in HD are of
∗
Not associated with neurodegeneration.

interest, as psychosis or a personality change toward
suspiciousness is often an early manifestation. Striatal
degeneration has been described as an early manifes-number of such cases. Many factors have been
tation, which begins in the medial aspect and spreads
described as determining psychosis in HD. Early age
but tends to spare the nucleus accumbens. The small
of onset is related to a higher incidence
[34].
Family
spiny neurons appear to be affected before the larger
history of schizophrenia is increased, and there are a
ones, with loss of dendrites being an early finding. In
number of reports of familial aggregation of SLP in HD

more advanced cases, changes have been described in
[35, 38, 39, 40].
Correa and colleagues
[41]
reported
the globus pallidus, subthalamic nucleus, red nucleus,
the association of HD and psychosis in three genera-substantia nigra, and the cerebellum. The medium
tions in one family.

spiny neurons are GABA-ergic and provide inhibitory
input from the striatum to the globus pallidus. How
Genetics

their degeneration could lead to psychosis can only
Because of the high prevalence of psychotic symptoms,
be speculated upon. It is possible that striatal sen-the frequency of trinucleotide repeats has been exam-sitivity to dopamine changes as a consequence, and
ined in schizophrenia. The phenomenon of anticipa-such a change in the medial aspects may be related
tion has been reported in pedigrees of schizophre-to the development of psychosis. The development
nia
[42].
Repeat Expansion Detection techniques have
of chorea has been related to increased dopamin-suggested an increased number of triplet repeats
ergic activity, as is suggested by similar involuntary
in schizophrenia
[43, 44].
Studies of (CAG)n in
movements produced by dopaminergic drugs. How-schizophrenia have however not reported an increase
ever, loss of GABA inhibition may produce the same
of repeats
[45, 46].
Moreover, the HD patients who
result. The loss of GABA in the striatum also alters
develop psychosis do not have repeat numbers dif-this activity in fronto-subcortical circuits that under-ferent from those without psychosis
[47, 48].
The
lie behavioral syndromes
[51].
In children and young
only reported association of (CAG)n with schizophre-adults with chorea and behavioral disorders, the sub-nia is that with the gene for dominant spinocerebel-thalamic nucleus had been reported to be markedly
lar ataxia 1 at chromosome 6pter-p22
[49],
but this
affected.

awaits replication. Other proteins with (CAG)n that
In the cortex, layers 3, 5, and 6 suffer neuronal loss,
are candidate genes for schizophrenia are Pim-1 proto-with reduced numbers as well as neuronal size, and
oncogene, alkaline phosphatase, TATA-binding pro-an increase in glial numbers
[52].
In schizophrenia,
tein, and brain natriuretic protein
[50].

there is a downward shift in neuronal size in layer 3,
352

Chapter 28 – Huntington’s Disease and related disorders

with an increased density of small neurons
[52].
This
with restraint in this patient group
[60].
Patients gen-change is evident in the frontal cortex but not in the
erally need long-term treatment. Because the longitu-occipital cortex. There is no evidence that degenera-dinal course of psychosis in patients has not been well
tive cell loss occurs in the schizophrenic cortex. There
charted, firm recommendations are difficult to make.

are therefore significant differences in the pathology of
Irritability may also respond to atypical neuroleptics.

the two disorders, although some similarities exist,
HD patients may need treatment with other drugs
possibly in the early stages of the disorders. Further
such as antidepressants or antiepileptic drugs. GABA-work on the pathology of schizophrenia is neces-ergic drugs such as benzodiazepines, baclofen, and val-sary to understand the significance of any similarities.

proic acid have not been noted to be beneficial for
Furthermore, the neuropathological correlates of psy-psychosis, motor disorder, or cognition. Newer drugs
chosis in HD may shed some light into the pathome-being developed for the disorder target the patho-chanisms of schizophrenia.

physiological process. One such drug is cystamine,
which is an inhibitor of transglutaminase and has been
Neuropsychology

shown to reduce tremors and prolong life in mice
with the mutant HD gene
[61]
. There are many other
The cognitive deficits of schizophrenia resemble the
substances in clinical trials for HD, which include
subcortical cognitive syndrome of HD. Schizophren-the antibiotic minocycline and the dietary supplement
ics have deficits in executive function, they have mem-creatine
[61].

ory problems that are not the most salient of their
deficits, they show slowing in their thinking, and their
motor skills are impaired
[53, 54].
Rates of depression
Other trinucleotide repeat disorders

are higher in schizophrenia, just as they are in sub-The trinucleotide disorders are broadly divided into
cortical syndromes
[51].
Not all authors agree, how-two categories
[33]
: (i) the polyglutamine (polyQ)
ever, that schizophrenia is characterized by subcorti-repeat disorders, in which the expanded polyQ com-cal dysfunction, and many investigations suggest that
ponent of the protein results in a toxic gain of func-the cognitive dysfunction of schizophrenia is better
tion leading to neurodegeneration, the classic example
accounted for by fronto-temporal dysfunction
[55].
It
being HD discussed above; and (ii) disorders in which
is possible that, despite their differences, HD patients
the triplet repeats occur in an untranslated region of
may develop neuropsychological deficits that resemble
the gene, leading to various mechanisms, including
those in schizophrenia and this might provide the sub-gene suppression. These are summarized in
Table 28.2.

strate for the development of psychotic symptoms in
The spinocerebellar ataxias (SCA) are a group of 25

HD.

disorders, eight of which are due to a triplet repeat disorder
[33].
The SCA gene codes for ataxin. There has
Treatment

been much interest in the psychiatric features of SCA,
The psychosis associated with HD usually responds
which stems from the appreciation that the cerebellum
to neuroleptic medication, which is also known to
makes a significant contribution to cognition
[62, 63].

suppress the involuntary movements of HD
[56].

In a report of 133 patients with cerebellar degenera-Haloperidol, a potent dopamine D2 antagonist, has
tion, 30% had cognitive deficits and 41% had noncog-been one of the more commonly used drugs in the
nitive psychiatric symptoms
[64].
In a further report
past. Because of its propensity for extrapyramidal side
from the same group, 31 patients with spinocerebellar
effects, a number of atypical drugs such as risperi-degeneration were compared with 29 healthy subjects
done
[56, 57],
olanzapine
[58]
and sulpiride
[59]
have
[17].
The rate of all psychiatric disorders in the former
been tried, with good results generally reported in
was 77%, being predominantly mood disorder. One
the literature. Doses of risperidone used are typi-case of schizophrenia and two cases of psychotic dis-cally 2–4 mg/day, and equivalent doses are recom-order not otherwise specified were noted. The authors
mended for the other drugs. Clozapine may be used
suggested that the psychosis might be a consequence
to treat the psychosis, but it has little beneficial effect
of the cerebellar dysfunction leading to a “dysmetria”

on chorea except in high doses. Because adverse reac-of thinking and pointed out to the studies of cere-tions are often encountered, clozapine should be used
bellar dysfunction in schizophrenia
[65].
Psychosis in
353

Organic Syndromes of Schizophrenia – Section 3

cerebellar degenerative disorders has been reported by
tion has been of interest to geneticists and the field was
other authors as well
[66]
, although the literature on
reviewed in 2000
[67].
This review ruled out a major
this topic is limited.

role for triplet repeats in the etiology of schizophre-The association of SCA with SLP further raises the
nia, but did not rule out a modest role in a minority of
issue of triplet repeats and their role in the genetics
cases. The field needs further work, as was discussed in
of schizophrenia. As mentioned above, this associa-Chapter 23 of this book.

354

Chapter 28 – Huntington’s Disease and related disorders

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