Medical Hypotheses 73 (2009) 259–262

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Exogenous nicotine normalises sensory gating in schizophrenia;

therapeutic implications
J.L.C. Conway
MRC SGDP Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, United Kingdom

a r t i c l e i n f o s u m m a r y

Article history: There is a current popular recognition that cigarette smoking is deleterious to health. Although this is
Received 16 January 2009 very clearly the case for physical health, the situation regarding mental health is, however, rather more
Accepted 18 February 2009 complicated. This piece concentrates on the role of smoking in schizophrenia: it is important to consider
why schizophrenia, exceptionally amongst the severe and enduring mental illnesses, is associated with
increased cigarette consumption. People who suffer from schizophrenia consequently have a greater risk
of the complications to physical health caused by this addiction and clearly, it is important to understand
why this occurs. Numerous investigators have found that both neuroleptic-naïve, first-onset schizo-
phrenics, together with chronic sufferers of the illness, consume more cigarettes and extract a greater
amount of nicotine from them. Researchers have further determined that there is deficient endogenous
central nicotinic neurotransmission in schizophrenia, which causes a disruption of sensory gating. This
disrupted sensory gating is a reasonable explanation for the delusional misinterpretation of consequent
cerebral events. This is the principal reason for the markedly increased rate of cigarette smoking in people
with schizophrenia: tobacco cigarette smoking represents an attempt at self-medication in schizophre-
nia, because the additional nicotine so provided alleviates the hypofunctional sensory gating seen in this
illness. Nicotine has been proposed to alleviate negative symptoms. The hypothesis here proposes that as
nicotine alleviates positive symptoms, it consequently also – ultimately – prevents negative symptoms
caused by the apoptotic effects of excitotoxicity. It would be worthwhile to investigate the therapeutic
effects, if any, of additional exogenous nicotine delivered in a less toxic form than cigarettes.
Ó 2009 Elsevier Ltd. All rights reserved.

Introduction several workers interested in the neurophysiology of schizophre-

It is a familiar fact that large numbers of people with schizo-
phrenia smoke. A recent article in the Journal of the American
Medical Association [1] indicates that the area remains one of cur-
rent clinical interest. This is one of several articles which indicate
the consequent increased risks to health as a result of smoking in
people with schizophrenia. Numerous studies have shown that
the rate of smoking in such people is much higher than those with
other psychiatric diagnoses [2,3]. As such, people with schizophre-
nia have a much greater risk of complications of tobacco cigarette
smoking – especially severe respiratory and cardiovascular disease
[4]. Indeed, the ban on smoking which began in January 2006 with-
in NHS premises (together with all public places) adds a topical
dimension to the particular issue of smoking and schizophrenia.
Consideration of the reason for the increased level of smoking is
important: it is quite possible that the pharmacological reason
for this is that they are supplementing their supply of endogenous
nicotinic agonists [5]. This is a view which has long been shared by
E-mail address: jackie.conway@doctors.org.uk
nia, and is exemplified by Tamminga [6], who edited a review of
the current state of biochemical knowledge on schizophrenia in
1999. A review by Punnoose and Belgamwar for the Cochrane Col-
laboration [7], first published in 2006, undertook a statistical anal-
ysis of the available data on nicotine as a therapeutic agent in
psychotic illnesses such as schizophrenia. Unfortunately their sta-
tistical inclusion criteria were so rigorous that these authors did
not find a single study which was eligible for inclusion in the re-
view section of their paper. Thus, they did not go on to consider
the possible neurophysiological reasons for the use of nicotine in
schizophrenia. While paying due attention to the statistical criti-
cisms identified by these authors, the primary question should
have been to try to understand the possible stimuli for the pro-
foundly increased consumption of nicotine seen in schizophrenia.
That is what this article proposes to do. It will commence by intro-
ducing the general background to smoking in schizophrenia. Re-
cent work on sensory gating and excitotoxicity will strengthen
the case for the therapeutic use of nicotine in schizophrenia. After
discussing some of the genetic implications of the large body of
work to date on schizophrenia, the therapeutic implications of this
work will be summarised.

0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2009.02.017
260 J.L.C. Conway / Medical Hypotheses 73 (2009) 259–262
Smoking and schizophrenia
Schizophrenia confers a need for supplementation of endogenous
nicotinic agonists because of the nicotinic – cholinergic – hypofunc-
tion which is part of the pathology of this disease [4]. If this is indeed
the case, then other methods for delivering the additional nicotine
can be explored. The health benefits of delivering additional nicotine
by a method other than cigarette smoking should be obvious. How-
ever, to clearly reiterate the well-known causal association between
smoking and respiratory pathology, the seminal study by Doll and
Bradford Hill in 1952 (Quoted, for example, in 1984, [8]) indicates
that lung cancer is directly attributable to tobacco cigarette smoking.
This finding has been replicated on numerous occasions and is now
accepted as common knowledge, understood by the general public.
Recent lurid anti-smoking advertising campaigns are an additional
demonstration of this understanding.
To recap, there is a popular current recognition of the general dam-
age caused by smoking to physical health. This is one of the reasons
which underlie the current ban on smoking within NHS premises.
The carcinogenic factors in cigarettes have been found to be the tar,
carbon monoxide and carbon dioxide produced while the cigarette
is burning. Inhalation of these substances is toxic to the respiratory
system. The recognition that nicotine, as a component of tobacco cig-
arettes, is something which might prolong the addiction to them has
eventually led to nicotine becoming available in less toxic formula-
tions, such as via adhesive skin patches, or as chewing-gum, for people
who are attempting to stop smoking. While such formulations remain
contraindicated for retail sale to people with unstable cardiovascular
disease, the Committee on the Safety of Medicines has deemed these
preparations to be safe enough for general retail sale without pre-
scription, in high street pharmacies. Discussion with the pharmacist
would let a member of the public know whether or not they need to
discuss the situation with another health professional, such as their
GP, before purchasing nicotine replacement therapy.
To return to the specific instance of smoking in people with
schizophrenia, the number of psychiatric in-patients with this
diagnosis who smoke has been repeatedly recorded to be far in ex-
cess of that expected. Kelly and McCreadie, for example, in 1999
[9], found that 88% of in-patients with schizophrenia smoked.
Superficial explanations for the high number of in-patients smok-
ing often centre on the lifestyle on the ward. This is especially
the case for the longer-stay rehabilitation environments. Here, a
simplistic explanation for this behaviour would be that there is lit-
tle else to do on the ward, or that peer pressure from other patients
encourages smoking. It must be stated at this point that Kelly and
McCreadie do not propose such explanations; they suggest that the
excessive rate of smoking is related to the neuropathology of
schizophrenia and ‘‘. . .may be a marker for the neurodevelopmental
form of the illness. . .” (ibid.). The fact remains that this level of
smoking is much higher than that of the general population, and
indeed of other psychiatric patients [10].
Smoking reduces plasma neuroleptic levels via induction of he-
patic microsomal enzymes and by increasing renal clearance. Cer-
tainly, when the older antipsychotic drugs were commonly used,
this could have been another explanation for the increased level
of smoking in people with serious psychoses: faster breakdown
of administered drugs necessarily reduces their potential for
unpleasant side-effects. Newer formulations of antipsychotic drugs
have, generally, fewer unpleasant side-effects (such as extrapyra-
midal dystonias). Importantly, though, there is an increased prev-
alence of cigarette smoking even in drug-naïve, first-onset
schizophrenics [11]. This implies:
‘‘. . .that smoking produces direct ‘therapeutic’ effects (i.e., indepen-
dent of it’s interactions with antipsychotics) for patients with
schizophrenia.” [11].
Therefore, the ‘ward lifestyle’ explanation is clearly an inade-
quate explanation for the increased rate of smoking in schizophre-
nia. McEvoy and Brown (ibid.) indicate a role for nicotine with
direct implications in the pathology of schizophrenia.
Neurophysiology of schizophrenia: sensory gating
Cigarette smoking could be understood as a form of self-medica-
tion in schizophrenia (e.g. [6,12]). It appears that, in schizophrenia,
there is defective central nicotinic neurotransmission [4,5,13–15].
Nicotine appears to stimulate dopamine release in the mesolimbic
system. Therefore, one might conclude that smoking, or delivery of
additional nicotine in other ways – such as chewing-gum or epider-
mal patches – could worsen the symptoms of acute schizophrenia.
However, a closer investigation of the neurophysiological role of nic-
otine reveals that it is also determinate in the differentiation of neu-
ronal impulses from differing sources. At inhibitory cerebral
neuronal sites, such as at CA3 [area 3 of the Cornis Ammonis] in
the hippocampus, particularly, the a7 nicotinic cholinergic receptors
in the inhibitory hippocampal neurones appear to be important in
the function of working memory and sensory gating [5,15,16]. In
other words, increased inhibition is permitted by a higher rate of
neuronal firing here. The nicotinic receptor is a ligand-gated ion
channel: the ligand is nicotine and the ion is calcium (Ca2+). Influx
of the calcium ion into this type of hippocampal neurone – usually
an interneurone – results in the secretion of GABA (gamma-amino
butyric acid) into the synaptic cleft. GABA is the predominant inhib-
itory cerebral neurotransmitter. Therefore, nicotinic receptor activa-
tion permits increased neurotransmission at inhibitory sites. When
a group of nerve impulses within the general ‘neuronal chatter’ of the
brain is inhibited, this can be an example of sensory gating at work. A
formal definition of sensory gating is given in the review by Potter
et al. [17]:
‘‘. . .Sensory gating refers to the pre-attentional habituation of
responses to repeated exposure to the same sensory stimulus.”
[my emphasis].
Efficient sensory gating allows a person to ’screen out’, or ignore
background stimuli, such as the noise of a ventilation motor, or traf-
fic outside a window. If the person is unable to do this, as in acute
schizophrenia, the now intrusive stimulus may acquire a delusional
significance. This is explicable by the pathological cerebral function-
ing which occurs in schizophrenia: delusions represent a conscious
attempt by the person to comprehend the contemporaneous neuro-
physiological events in his/her brain. Correctly functioning sensory
gating stops the possible misinterpretation of cerebral events. Atten-
tion is directed towards the incoming stimulus, and remains there
until initial processing is completed. Correctly functioning sensory
gating further allows the individual to differentiate between inter-
nally-generated and externally-generated experience. The first-rank
symptom of hearing one’s thoughts spoken aloud is a perfect illus-
tration of dysfunctional sensory gating. If gating does not function
correctly, as is hypothesised in schizophrenia, misattribution of
experience can – perhaps understandably, as explained above – lead
to hallucinations or delusions [15]. To summarise, therefore, when
functioning correctly, activation of the nicotinic a7 receptors in
GABA-ergic neurones at area CA3 of the hippocampus reduces
schizophrenic symptoms [13]. This is confirmed by Garcia-Anaya
et al. [16], who emphasise the pathological importance of dysfunc-
tional sensory gating in acute schizophrenia.
Excitotoxicity and apoptosis
One explanation for positive symptoms in schizophrenia is that
there is some neuronal over-activity in the mesolimbic system. As
 J.L.C. Conway / Medical Hypotheses 73 (2009) 259–262
previously implied, this is probably an over-simplification: defi-
cient sensory gating might be a better explanation for positive
symptoms. Negative symptoms, by contrast, which essentially rep-
resent a deficiency in normal cognitive function, can be explained
by excitotoxicity [20]. This is exactly analogous to the situation
occurring in status epilepticus: unremitting stimulation of the neu-
rone leads to exhaustion of its contents, which triggers processes
encoded in the cellular DNA – probably at the telomere – resulting
in cell death. Thus, excitotoxicity triggers apoptosis. This could be
one of the pathological processes operative in schizophrenia; a loss
of inhibition by inhibitory neurones leads, perhaps, to cell death by
the triggering of apoptotic mechanisms. Apoptosis is the process by
which a cell ‘self-destructs’, following the instructions in its DNA
after a suitable event. Cells such as astrocytes may then ‘mop up’
the neuronal material which is no longer active, in the same way
that a peripheral macrophage clears up non-functional cellular
material. Clearly, there can be a genetic contribution to this pro-
cess. Perinatal insult to the developing nervous system may also
be relevant here. Certainly, especially in the late 1980s and early
1990s, there was great interest in the potential developmental
neurotoxicity of the influenza virus in mothers who had not been
previously exposed: this was submitted at the time to be one of
the reasons why the children of first-generation Caribbean moth-
ers who had migrated to north-western Europe had a greater po-
tential risk of schizophrenia. There has since been much greater
recognition of the influence of social and psychological stresses
in this social group, leading to this specific instance of the ‘influ-
enza and schizophrenia’ theory having been disregarded. A careful
study by Mednick and co-workers [21] addressed the criticisms of
earlier studies on this topic, investigating people with schizophre-
nia born after the 1957 pandemic and their history of pre-natal
infection. Nevertheless, the general topic of pre-natal viral infec-
tion and the development of schizophrenia in those infected re-
mains an area of research interest (e.g. [22]). In contrast, this
article concentrates on the neurophysiology of established schizo-
phrenia and in particular, the symptomatic role of nicotine here.
Importantly, although apoptosis is a physiological process
which is necessary in, for example, the profound synaptic and neu-
ronal remodelling in human adolescence, in schizophrenia, there
may well be a disruption of the normal apoptotic process [23].
The cumulatively deleterious effect of every acute exacerbation
of schizophrenia can be explained by the proposition that each at-
tack further destroys cerebral neurones via excitotoxic mecha-
nisms [20]. This is the probable explanation for the cortical
atrophy commonly seen in sufferers of chronic schizophrenia.
The cumulative neuronal loss is manifest as negative symptoms,
some of which can be seen in a first attack of the illness. The
presence of negative symptoms in a first episode of schizophrenia
indicates the extremely aggressive nature of the underlying patho-
logical process. It also explains the poor prognosis in those people
with schizophrenia who are not compliant with their medication.
The rationale behind antipsychotic medication is to halt the
underlying pathology of the illness – a fact which is often lost in
the process of its administration and continuation.
The fact that nicotinic receptor stimulation permits correctly
functioning sensory gating suggests that the process might also
be useful in addressing the negative symptoms of schizophrenia.
Indeed, this is where most researchers interested in the therapeu-
tic use of nicotine for schizophrenia have seen its ultimate utility.
Excitation of inhibitory neurones is the specific process concerned:
unremitting mesolimbic stimulation is prevented [24] and there is
no neuronal loss because of excitotoxicity, as explained above. To
précis this, there are positive symptoms which precede the nega-
tive symptoms of schizophrenia. The duration of untreated psycho-
sis (DUP) is also important. A longer DUP allows more cerebral
damage to occur, as a result of excitotoxic apoptosis. Therefore,
261
I think that it is reasonable to propose that by permitting sensory
gating to function correctly, positive symptoms are arrested first.
This, of course, is the rationale for the administration of antipsy-
chotic drugs: to stop the pathological process. Positive symptoms
– which in themselves are undoubtedly extremely unpleasant for
the person concerned – are prevented. The pathological process
is thus arrested and no excitotoxically-triggered apoptosis can
occur, as there is no stimulus for it. Thus, the secondary negative
symptoms – and their consequent disabilities – do not occur.
Therefore in theory, a great deal of morbidity could be pre-
vented if treatment is adhered to.
Electrophysiological changes and genetics
As well as correcting the abnormality in sensory gating, detailed
above, caused by lowered numbers of nicotinic receptors, it seems
that smoking also causes an alteration in gene expression in people
with schizophrenia:
‘‘. . .Aberrant [gene] expression was observed for approximately 70
genes in non-smoking schizophrenia subjects, and expression was
normalised for these genes in smoking schizophrenia subjects.” [3].
This is a useful reminder of the dynamic nature of genes: genes
are not simply molecular instructions that act once (in the devel-
opment of the embryo) and then cease to function. They are con-
tinually available for action throughout the life of the organism.
Thus, the original self-medication hypothesis summarised by Tam-
minga in 1999 [6] remains further supported by several workers,
including Leonard and Adams (ibid.).
The dysfunction of sensory gating has been examined neuro-
physiologically by analysis of the P50 Evoked Response Potential, or
P50 ERP [12,15,18,19]. The P50 ERP is a measure on the electroen-
cephalogram which examines the cerebral response to two auditory
stimuli. The stimuli are given at different times, milliseconds apart.
The P50 ERP is: ‘‘. . .a neural response that manifests as a positive deflec-
tion over the [cranial] vertex, occurring approximately 50 ms post stim-
ulus.” [18]. In non-schizophrenic subjects, the response to the second
auditory stimulus will be diminished. This is taken to be evidence of
sensory gating at work. Although in this paradigm, the subject is not
presented with a long repetition of the sensory stimulus, as de-
scribed by Potter et al. [17], the P50 ERP is understood to be an elu-
cidation of the physiological process of sensory gating. The brain is
processing the first sensory impulse and therefore cannot attend
completely to a subsequent sensory impulse if it follows the first
too rapidly. People with schizophrenia and their first-degree rela-
tives show a loss of inhibition of the second P50 ERP which is said
to demonstrate deficient sensory gating. As stated above, a7 nico-
tinic cholinergic receptors in the hippocampal CA3 region must
function correctly in order for efficient sensory gating to occur. Cer-
tainly, the lack of pre-pulse inhibition of the second P50 ERP is a firm,
reproducible biological marker for a genetic susceptibility to schizo-
phrenia [19]. The fact that the first-degree relatives of people with
schizophrenia show the same electrophysiological abnormalities
in information processing, but do not suffer from schizophrenia,
indicates that the interaction of several simultaneous factors is
necessary for the disease to express itself. These could include a
triggering of possible neurodevelopmental abnormalities caused
by pre-natal maternal infection, as well as social and psychologi-
cal stressors. The latter two will of course have a neurological
consequence.
Therapeutic implications
The propositions above lead one to conclude that there is a
reasonable case for further investigating the role of nicotine in
262 J.L.C. Conway / Medical Hypotheses 73 (2009) 259–262
schizophrenia. The particular importance of a7 nicotinic cholin-
ergic receptors in schizophrenia has been recognised for a num-
ber of years now [6,25], and remains a current topic of interest.
The enhancement of nicotinic neurotransmission by agents such
as galantamine has led to the consideration of these agents as
adjuvants in the treatment of schizophrenia [26,27]. There is,
additionally, a possible utility in investigating the importance
of additional nicotine from a less toxic administrative form than
cigarettes in people with schizophrenia. Perhaps it is surprising
that there has not been more research on the specific use of
agents such as nicotine skin patches, or nicotine chewing-gum
in schizophrenia. One such study, in 2004, by Chou et al. [28],
investigated nicotine skin patches for prolonging smoking cessa-
tion in-patients with schizophrenia. A similar study, by George
et al. [2], also looked at the usefulness of nicotine skin patches
and the cessation of smoking in people with schizophrenia.
The work carried out by the group including Postma and Kumari,
in the UK, addresses the particular issue of the symptomatic
influence of nicotine in schizophrenia. There has been some
important work hitherto on the importance of nicotine in cogni-
tive function [5,15,19]: the cognitive functions of nicotine in-
clude allowing efficient neuronal inhibition to occur at the
correct sites. In this way, sensory gating functions accurately,
allowing the conscious differentiation of sensory experience from
different sources. I would further propose that by allowing
sensory gating to function correctly, nicotine also alleviates some
positive symptoms of schizophrenia, namely delusions and
hallucinations, which represent a conscious attempt by the af-
fected person to make sense of his/her coincidental cerebral
phenomena.
As explained here, nicotine at the a7 receptor sites of area CA3
of the hippocampus permits sensory gating to operate efficiently.
In this way, habituation to repeated sensory stimuli [17] allows
these not to dominate one’s attentional focus. Thus, an aspect of
positive symptomatology in schizophrenia is reduced.
Importantly, the preceding point is still valid: there has not
been a systematic investigation of the influence of exogenous nic-
otine on schizophrenic symptoms. Potter et al. [17] observe that
there has been a notably inadequate amount of specific work to
clarify the exact nature of the influence of nicotine on sensory gat-
ing as measured by the P50 ERP paradigm. They further state that
the majority of work examined in their thorough review was eval-
uated by non-blinded raters. In addition, ‘‘. . .nicotine use is rarely
reported or analysed as a potential confounding variable” (ibid.).
Hence, there is a clear direction for further work in this area.
Attention is once again drawn to the point made in the section
above on excitotoxicity and apoptosis: a longer DUP results in
more cerebral damage, which ultimately leads to more disability.
Indeed, I would go so far as to state that further research in this
area is an ethical imperative, because a great deal of morbidity,
both physical and mental, could be prevented.
In summary, the ideas above lead to the conclusion that an in-
crease in nicotinic activity might alleviate some schizophrenic
symptoms. It would be worthwhile to investigate the symptomatic
effects – if any – of nicotine skin patches or chewing-gum on
schizophrenic symptoms. This could then elucidate a possible
adjunctive treatment for schizophrenia which is perhaps very
acceptable to the patient group concerned. The use of, e.g. nicotine
patches as an adjunctive treatment for schizophrenia would, it is
presumed, reduce the amount of cigarettes smoked by sufferers
of this condition. Therefore, both the physical health and the men-
tal health of this vulnerable patient group could be improved.
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