Secondary Schizophrenia (42 page)

and so on;

d. Hysteria-motor, sensory, astasia-abasia, and so
Limbic kindling

on;

One of the most discussed explanations for FN is
3a. A reduction in the total number of spikes by more
amygdaloid and limbic kindling, or occurrence of sub-than 50%, when compared to a similar recording
threshold seizures that in turn result in long-term
performed during a normal state of behavior
potentiation of synapses
[13, 15].

counted in a 60-minute awake EEG recording,
Kindling defines a mechanism by which repeated
performed using a 16-channel machine and the
(daily) brief, high-frequency trains of electrical pulses
standard 10–20 system of electrode placement;
to limbic and cortical areas produce a change in
OR

response to the stimulus, such that the latter elicits
3b. A report of complete cessation of seizures
a motor convulsion that outlasts the stimulus train.

corroborated by a relative or caregiver.

Thus, when a current of low amplitude but high pulse
frequency is applied to the amygdala, a region of great
Supportive criteria include:

susceptibility, there is a gradual stepwise progression
1. A recent change (within 30 days) of the
of behavioral and EEG responses that finally culmi-pharmacologic regimen;
nate in a full motor seizure. Kindling thus results in a
2. Report of similar episodes of seizure cessation and
progressive behavioral sequence that follows the EEG

behavioral disturbance in the past, from a close
changes.

relative, caregiver, or general practitioner – or
Although electrical kindling has gained acceptance
documentation of this in hospital records, with or
as a useful model for understanding epilepsy, it has
without EEG evidence. This may or may not be
also been postulated that pharmacologic kindling and
105

linked to anticonvulsant drugs.

behavioral sensitization may be a used to explain
Organic Syndromes of Schizophrenia – Section 3

psychosis in human epilepsy. A number of pharmaco-Psychosis
logic compounds have been shown to produce behav-Dopamine
ioral responses, beyond their documented pharmacologic effects. It has been postulated that the end-GABA Glutamine

point for pharmacologic kindling may be a particular form of affective expression or behavior, unlike
Seizures

electrical kindling that terminates in a motor seizure.

Figure 7.1
Role of various neurotransmitters in psychosis and
Stevens and Livermore
[16]
and later Sato and col-seizures: putative relationships.

leagues
[17]
developed interesting experimental models whereby they demonstrated that pharmacological
kindling, with the use of various dopamine agonists,
demonstrated in kindling) and a behavioral expression
antagonists, and catecholaminergic agents can modify
may then predominate
[18].

behaviors.

The process of kindling involves the spread of
seizure activity from the site of stimulation to other
Role of neurotransmitters

areas of the CNS. It has therefore been postulated
A number of neurotransmitters encourage this antag-that it may be a potential mechanism by which focal
onism between seizure and psychosis. Dopamine
epilepsy may lead to a more generalized effect on
remains the neurotransmitter most consistently and
behavior and psychosis. The development of epilepti-definitively exemplifying the antagonism between psy-form activity in areas of the brain that receive synaptic
chosis and seizures. Dopamine, being inhibitory in
input from the epileptic focus, the development of sec-nature, reduces the hyperexcitability associated with
ondary foci, is called secondary epileptogenesis. There
seizures and is psychogenic in nature. Glutamine as a
is no convincing hypothesis to explain how kindling
possible culpable neurotransmitter is gaining impor-might lead to secondary epileptogenesis. One mech-tance. Enhanced glutaminergic excitation is a potential
anism that has been proposed is the phenomenon of
epileptogenic mechanism, particularly with respect to
long-term potentiation (LTP). LTP is the enhancement
the N-methyl-D-aspartate (NMDA) glutamate recep-of synaptic activity after high-frequency stimulation of
tor. Both electrical kindling and LTP involve activation
an afferent pathway. The enhancement of synaptic effi-of the excitatory amino acid (probably glutaminergic)
cacy is specific to the input that has been tetanized (it
pathways involving NMDA receptors. In schizophre-is homosynaptic), and therefore the postsynaptic neu-nia, on the other hand, an endogenous antagonist
rons respond to other stimuli normally. In the Stevens
at the NMDA receptor, N-acetyl-aspartyl-glutamate,
and Livermore experiment, kindling of the Ventral
appears to have enhanced activity in the frontal cor-Tegmental Area (VTA) in cats produced electrophysi-tex and hippocampal formation. Interestingly, this
ologic changes that correlated with behavioral change.

hypothesized dysfunction of glutaminergic transmis-They thereby postulated that because stimulation of
sion also interdigitates with the traditional dopamine
the VTA resulted in increased dopamine release in
hypothesis of schizophrenia. Presynaptic dopamine
the limbic system and neocortex, kindling in the VTA
receptors on corticostriatal and limbic glutaminer-might result in potentiation of dopamine transmis-gic terminals provide a negative regulation of gluta-sion. If psychosis in patients with epilepsy, at least to
mate release. Neuroleptic blockade of these presynap-a significant extent, were a manifestation of enhanced
tic receptors may thereby enhance glutaminergic input
dopamine transmission, then spread of seizure activ-to the caudate and putamen and to other forebrain
ity to the VTA may well explain the development of
regions receiving dopaminergic innervation. Loss of
psychosis through secondary epileptogenesis. It is pos-GABA inhibition is another potential epileptogenic
sible to envision a role for secondary epileptogene-factor; AEDs that increase GABA levels are associated
sis in the development of psychopathology in patients
with the development of a psychopathologic state in
with epilepsy. If a new site of epileptic activity were to
up to 10% of patients, characterized by mood changes,
develop distant to the original focus that led to seizure
agitation, and even psychotic symptoms of a paranoid
expression, and if that site was one in which seizures
nature. Catecholamines such as norepinephrine and
were poorly expressed, this may well lead to inhibition
serotonin, as well as peptides, may also play a role in
106

of epileptic activity in the primary focus (as has been
FN
[14].
See
Figure 7.1.

Chapter 7 – Understanding the pathophysiology of schizophrenia

An important observation, not clearly evident
such as the hippocampus provide an important loss of
from the illustration, is that although epilepsy is
inhibitory control leading to enhanced seizure activity.

believed to be a consequence of glutaminergic pre-However, it also activates important feedback mech-ponderance and GABAergic deficit, the converse is
anisms through the
κ
opioids
[23].
However,
κ
opi-believed to be true for schizophrenia. Attempting to
oids can significantly reduce prepulse inhibition that
understand this impairment leads us to a neurode-has been known to induce perceptual abnormalities
velopmental affliction on the GABAergic interneu-and thus have been identified as having psychotogenic
rons
[19].
The GABAergic neurons, unlike the usual
potential.

inside-out pattern of development of the pyramidal
layer, migrate tangentially outward from the thalamus
[20].
This migration is affected by perinatal neuros-Channelopathy
teroids, which also affects normal lamination. These
A recent hypothesis
[14]
gains support from evidence
interneurons are the anatomical or functional targets
of abnormal ion channels in episodic neuropsychiatric
for (basal forebrain) cholinergic (ACh) and/or brain-disorders. Ion channels provide the basis for regulation
stem raphe nucleus serotonergic (5-HT) neurons. The
of excitability in the central nervous system. Muta-cortical GABAergic system plays an important role
tions in ion channels have been implicated in various
in cortical development and localization of different
epilepsy syndromes, including autosomal dominant
types of interneurons relative to one another, thereby
nocturnal frontal lobe epilepsy (neuronal nicotinic
influencing cortical networks and functioning. These
acetylcholine receptor), benign familial neonatal con-cells provide both inhibitory and disinhibitory modu-vulsions (potassium channels), generalized epilepsy
lation of cortical and hippocampal circuits generating
with febrile seizures plus (sodium channels or the
oscillatory rhythms that affect gating of sensory infor-GABA (A) receptor), and episodic ataxia type-1, which
mation within the corticolimbic system. Morphologi-is associated with epilepsy in a few patients (another
cal changes in the GABAergic interneurons have been
type of potassium channel). That ion channels are
noted in postmortem studies of schizophrenic brains.

expressed in the limbic regions of the brain, with a
Besides developmental influences, stressful condi-putative role in behavior and that a number of AEDs
tions that modulate that dopamine system causing
influence ion channel functioning, leads one to specu-ingrowths of extrinsic afferents, such as the mesocor-late whether “forced normalisation of the EEG with its
tical dopamine projections, may “trigger” the appear-associated behavioral changes is the phenotype, albeit
ance of a defective GABA system
[21].

rarely expressed, of a channel disorder”
[14].

Cannabinoid and opioid receptor systems
Apoptosis and vascular dysfunction
Endogenous cannabinoids have been shown to have
Recurrent limbic seizures lead to an increased expres-antiepileptic potential, whereas cannabis is known
sion of messenger ribonucleic acid (RNA) for c-fos and
to cause transient psychotic states. This raises the
nerve growth factor (NGF) that in turn can result in
possibility that an increase in endogenous cannabi-expansion of glutamatergic presynaptic mossy fibers
noids in the synapse accompanying seizure cessation
and an increase in postsynaptic densities on gran-can result in the development of psychopathology.

ule cell dendrites
[24].
Recurrent kindling on a back-Cannabinoids activate the dopaminergic neurons in
ground of this altered glutamate activity can result
VTA that form the main ascending projections of
in programmed cell death or apoptosis
[25].
Another
the mesocorticolimbic dopamine system and modu-possible explanation, encouraged by SPECT studies,
late GABA and glutamate transmission through presy-is a process of slow vascular compromise, proceeding
naptic CB1 receptors
[22]
. Both these neurotransmit-further to programmed cell death or apoptosis. With
ter systems, that is, the mesolimbic dopaminergic and
alteration in membrane dynamics because of apop-glutamatergic systems, have been implicated in the eti-tosis, channelopathies, deoxyribonucleic acid (DNA)
ology of schizophrenia. Akin to endogenous cannabi-fragmentation, and mitochondrial dysfunction can
noids,
κ
opioids have been found to have antiepileptic
occur, resulting in chaotic release of neurotransmit-potentials in experimental animal models. Recurrent
ters and the varied psychiatric manifestation of FN. See
107

seizures stimulating mossy fiber development in areas
Figure 7.2.

Organic Syndromes of Schizophrenia – Section 3

Recurrent seizure

Figure 7.2
Flowchart of mechanisms
linking recurrent seizures with apoptosis
and diverse psychiatric phenomena.

Increased expression of mRNA for c-fos

Expansion of glutamatergic presynaptic mossy fibers Increased exposure to excitotoxic glutamate

Kindling and subthreshold seizures

Seizures

Slow and low level exposure

Sudden, increased

Programmed cell death (apoptosis)

Measurement of

Necrosis

CSF caspase levels

Membrane changes

Mitochondrial dysfunction DNA fragmentation

Gliosis

Ion channel disturbances

Differential bioenergetics,

CSF analysis

(Channelopathies)

MRS studies

Chaotic release of neurotransmitters

Varied psychiatric presentation

The adenosine hypothesis

delicate balance in the distribution of adenosine may
be altered, leading to imbalances in the release of
Stimulation of adenosine receptors leads to inhibition
neurotransmitters and the psychopathology associated
through Ca
++
gated voltage channels, thereby inhibit-with FN.