Psychiatry Research 215 (2014) 497504

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Review article

Is elevated norepinephrine an etiological factor in some cases

of schizophrenia?
Paul J. Fitzgerald n
Department of Psychology, Texas A&M University, College Station, Room 3200 ILSB, TX 77843-4235, USA

ar t ic l e i nf o a b s t r a c t

Article history: A number of hypotheses have been put forth regarding the etiology of schizophrenia, including the
Received 9 May 2013 dopamine hypothesis, NMDA receptor hypofunction hypothesis, and others. A lesser known theory is
Received in revised form that elevated noradrenergic signaling plays a causative role in the disease. This paper briey re-examines
6 January 2014
the merits of this hypothesis, including as it relates to some recently published studies. Several lines of
Accepted 9 January 2014
Available online 18 January 2014
evidence are investigated, including: endogenous level studies of norepinephrine (NE); modulation of
the disease by noradrenergic drugs; association of the disease with bipolar disorder and hypertension,
Keywords: since these latter two conditions may involve elevated NE transmission; and effects of psychological
Clonidine stress on the disease, since stress can produce elevated release of NE. For many of these lines of evidence,
Guanfacine
their relationship with prepulse inhibition of startle is examined. A number of these studies support the
Propranolol
hypothesis, and several suggest that elevated NE signaling plays a particularly prominent role in the
Prazosin
Desipramine paranoid subtype of schizophrenia. If the hypothesis is correct for some persons, conventional
Yohimbine pharmaceutical treatment options, such as use of atypical antipsychotics (which may themselves
Paranoid schizophrenia modulate noradrenergic signaling), may be improved if selective NE transmission modulating agents
are added to or even substituted for these conventional drugs.
& 2014 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
2. Norepinephrine and metabolite level studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
3. Desipramine and other tricyclic antidepressant studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
4. Alpha2 adrenoceptor drug studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
5. Alpha1 adrenoceptor drug studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
6. Propranolol and other beta blocker studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
7. Bipolar disorder studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
8. Hypertension studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
9. Psychological stress studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
10. Additional data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
11. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Conicts of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502

1. Introduction of decades, a variety of biological theories have been put forth to

explain this severe neuropsychiatric disorder. These theories include
Identication of the precise etiological factors responsible for the widely known and intensely debated dopamine hypothesis of
schizophrenia remains a widely debated topic. Dating back a number schizophrenia, where both elevated and decreased dopamine trans-
mission have been posited (Carlsson, 1977; Grace, 1991; Carlsson
et al., 1997; Carlsson and Carlsson, 2006). A more recent, widely
n
Tel.: 1 443 564 1306. studied theory suggests that hypofunction of the glutamatergic
E-mail address: ptz@mbi.mb.jhu.edu NMDA receptor is a prominent causative factor in the disease

0165-1781/$ - see front matter & 2014 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.psychres.2014.01.011
498 P.J. Fitzgerald / Psychiatry Research 215 (2014) 497504
(Jentsch and Roth, 1999; Olney et al., 1999; Coyle et al., 2003). Yet
another theory, which may also relate to neurochemical causes of
schizophrenia, is that prenatal exposure to pronounced maternal
stress can have deleterious effects on neurodevelopment, predispos-
ing offspring to the disease later in life (Brixey et al., 1993; Kinney
et al., 2010).
There is a large body of data supporting these hypotheses (and
others), where they may interact with one another or with other
neurotransmitter systems in particular cases of schizophrenia
(Carlsson, 1977; Carlsson and Carlsson, 1989; Carlsson et al.,
1997). The dopamine hypothesis may be valid given the wide-
spread use and, to some degree, success of treatment with
antipsychotic drugs that partly achieve their effects by blocking
dopaminergic transmission (Attard and Taylor, 2012). However,
successful treatment by a particular biological mechanism of
action does not necessarily indicate etiology for that mechanism.
It is possible that other etiological factors exist, at least in a subset
of cases, where the identication of potential additional factors
may result in improvement in treatment, through use of pharma-
ceuticals and other methods.
This paper puts forth the hypothesis that elevated noradrener-
gic signaling is an etiological factor in some cases of schizophrenia.
Earlier studies have also suggested that elevated NE signaling plays
a pathophysiological role in schizophrenia (Yamamoto et al., 1994;
Yamamoto and Hornykiewicz, 2004; Lechin and van der Dijs,
2005). The current hypothesis suggests that an elevated synaptic
concentration of NE, present in particular brain circuits involved in
schizophrenia, is an etiological factor in the disease. The hypoth-
esis does not contradict the theories mentioned above, such as the
dopamine hypothesis or the NMDA receptor hypofunction hypoth-
esis, but rather suggests that elevated NE is an additional factor to
consider in understanding and treating the disease, at least in a
subset of persons (van Kammen and Kelley, 1991). A more general
variant of the elevated NE hypothesis is that elevated synaptic
transmission of NE, whether mediated by an increased synaptic
concentration of NE or by increased sensitivity of NE0 s postsynap-
tic receptor populations, is an etiological factor in some cases of
schizophrenia.
If elevated NE is an etiological factor in some cases of schizo-
phrenia, when and where in the brain does pathologically
increased signaling by this molecule take place? This paper is
suggesting that such elevation is largely genetic (Hui et al., 2013)
and present throughout the individual0 s life, although psychologi-
cal stress may exacerbate this effect (Myin-Germeys et al., 2002).
While the precise circuitry underlying the putative effect of
elevated NE on schizophrenia remains to be identied, one
possibility is that it involves dysregulated signaling in prefrontal
cortex (Robbins, 2005; Arnsten, 2011). Executive functional altera-
tions, such as impaired working memory, have been shown to
occur in schizophrenia (Barch and Ceaser, 2012). A number of
studies in macaque monkeys suggest that pharmacological mod-
ulation of alpha1 and alpha2 adrenergic receptors can alter work-
ing memory capability (Arnsten and Cai, 1993; Arnsten and
Jentsch, 1997; Arnsten et al., 1988). The noradrenergic neurons of
the locus coeruleus have been linked with cognition, including
through prefrontal mechanisms (Aston-Jones et al., 2000;
Chamberlain and Robbins, 2013). One possibility is that impaired
cognitive function in schizophrenia is partly mediated by altered
NE release in prefrontal cortex, acting at a molecular level through
the protein kinase C signaling pathway (Arnsten, 2004).
To assess the hypothesis, several lines of evidence are briey
presented below: endogenous level studies of NE and its metabolite
MHPG; modulation of the disease by drugs that increase or decrease
noradrenergic signaling; association of the disease with bipolar
disorder and hypertension, since these latter two conditions may
involve elevated noradrenergic transmission (Schildkraut, 1965;
Solt et al., 1990; Masuo et al., 2005); and effects of psychological
stress on the disease, since stress can produce elevated release of NE
(Hajos-Korcsok et al., 2003). For many of these lines of evidence,
their relationship with prepulse inhibition of startle (PPI) is also
examined, since this is a widely used assay in both animal models
and human studies of schizophrenia. The Pubmed database was
searched as recently as May 5, 2013. Keyword searches included the
following terms (typically combined with schizophrenia and
prepulse inhibition): (1) plasma/cerebrospinal uidconcentration,
(2) desipramine/tricyclic antidepressant(s)/clonidine/guanfacine/
yohimbine/prazosin/beta blocker(s)/propranolol, (3) pheochromo-
cytoma, (4) bipolar disorder proband(s), (5) hypertension
comorbidity, and (6) psychological stresscomorbidity. This is
certainly not meant to be an exhaustive review of the literature on
these topics, but rather to present some representative studies, many
of which support the hypothesis.
2. Norepinephrine and metabolite level studies
Blood and cerebrospinal uid (CSF) studies of persons with
schizophrenia (PWS) suggest that NE or its metabolites may be
elevated in the disease. In PWS compared with healthy controls,
where the PWS were unmedicated, serum levels of NE and dopamine
ranged from normal to more than three times that level for those with
the disease (Bondy et al., 1984). However, a comparison of PWS with
healthy controls found no difference in the CSF level of the NE
metabolite, MHPG (Gattaz et al., 1982). Plasma MHPG levels, measured
before and during 6 weeks of treatment with the antipsychotic drug,
haloperidol, showed a decrease in MHPG during treatment in good
responders to this drug (Chang et al., 1990).
A comparison of PWS and healthy controls found a higher level of
plasma NE in the disease, which correlated with global psychopathol-
ogy, positive symptomatology, and paranoia (Dajas et al., 1983). Other
investigators found higher levels of plasma MHPG during high
psychosis phases of the disease in comparison with times of lower
psychosis, and also found higher MHPG in persons with paranoid
schizophrenia relative to healthy controls (Ko et al., 1988). Elevated
levels of plasma MHPG declined with neuroleptic treatment in acute
schizophrenia, and this decrease correlated with a reduction in
positive symptomatology (Kaneko et al., 1992). CSF NE levels were
elevated in PWS relative to non-psychiatric controls, and PWS who
had high NE levels scored higher in a measure of positive symptoma-
tology (Kemali et al., 1990). A comparison of PWS and healthy matched
controls found plasma and CSF NE were signicantly higher in the
disease, particularly in paranoid schizophrenia (Kemali et al., 1982).
In drug-free PWS, CSF NE and MHPG levels correlated both with the
severity of negative symptoms and with psychosis ratings (van
Kammen et al., 1990).
In summary, many of the NE level studies described above
found elevations in NE or its metabolite MHPG in schizophrenia,
particularly during states of paranoia or positive symptomatology.
However, one possible confounding factor is that the disease may
produce psychological stress that feeds back on these measures
in PWS.
3. Desipramine and other tricyclic antidepressant studies
NE boosting antidepressants such as desipramine may alter
schizophrenia-related symptomatology, including PPI measures.
PWS who received 4 weeks of adjunctive treatment with the NE
boosting tricyclic antidepressants, amitriptyline or desipramine,
exhibited greater hallucinatory behavior and thought disturbance
than patients receiving placebo (Kramer et al., 1989). In contrast,
adjunctive desipramine treatment had benecial effects on both
 P.J. Fitzgerald / Psychiatry Research 215 (2014) 497504
mood and residual psychoticism in recovering PWS (Hogarty et al.,
1995). In a report on inpatient PWS, treatment with tricyclic
antidepressants was sometimes associated with increases in
paranoia (Jaroszynski et al., 1975). An assessment of completed
suicides in PWS found that 50% of these persons were taking full
dose tricyclic antidepressants (Gaertner et al., 2002).
PWS exhibit impaired sensorimotor gating, which when tested
manifests in reductions in PPI (Oranje et al., 2004). In a placebo
controlled study of healthy volunteers, acute treatment with
desipramine reduced PPI, consistent with there being enhanced
NE signaling in schizophrenia (Oranje et al., 2004). In contrast,
desipramine normalized amphetamine induced decits in PPI in
rats, whereas it failed to reverse phencyclidine (PCP; a psychoto-
mimetic NMDA receptor antagonist) induced decits (Pouzet et al.,
2005). In summary, there are mixed results on whether NE
boosting tricyclic antidepressants such as desipramine worsen
symptomatology in PWS or animal models, although perhaps
more evidence indicates worsening than improvement.
4. Alpha2 adrenoceptor drug studies
NE signal modulating alpha2 adrenoceptor agonist drugs such
as clonidine, which activate both presynaptic and postsynaptic
alpha2 receptors, may have therapeutic effects on schizophrenia-
related symptomatology. A double blind, placebo controlled, cross-
over study of seven PWS and one person with schizoaffective
disorder found that the antipsychotic effect of clonidine was equal
to that of standard neuroleptic drugs and better for tardive
dyskinesia (Freedman et al., 1982). In PWS who were also exhibit-
ing tardive dyskinesia, addition of clonidine to their treatment
regimen resulted in improvement in the dyskinesia (Tripodianakis
and Markianos, 1986). Hospitalized PWS were given double blind
treatment with clonidine, and after 3 weeks this drug produced
improvement in memory performance independently of a change
in psychosis (Fields et al., 1988). Also in hospitalized PWS, in this
case given clonidine or placebo added to haloperidol treatment,
the clonidine group showed signicantly greater improvement in
thought disorder symptomatology (Maas et al., 1995). Double
blind, placebo controlled administration of adjunctive guanfacine,
which is another alpha2 adrenergic agonist drug, improved spatial
working memory when paired with risperidone (Friedman et al.,
2001). However, in a preliminary double blind trial of clonidine,
two PWS became more agitated and aggressive while taking it
(Jimerson et al., 1980). In summary, the above clinical studies
suggest that clonidine and related drugs may produce therapeutic
effects in the treatment of some cases of schizophrenia.
Double blind treatment with clonidine in relapsed PWS produced
improvement in four of 13 patients, all of whom exhibited paranoid
schizophrenia (van Kammen et al., 1989). Drug challenge that com-
pared drug-free PWS with healthy controls found that clonidine
produced a greater than normal growth hormone response in para-
noid patients (Brambilla et al., 1994). In drug-free inpatient PWS, drug
challenge with clonidine produced signicantly lower prolactin and
thyrotropin release in the paranoid subtype of patients, as compared
with those in the disorganized subtype or in healthy controls (Mokrani
et al., 2000). These three studies further implicate dysregulated
noradrenergic signaling in paranoid schizophrenia.
In rats, a study using administration of PCP, where one of this
drug0 s effects is increasing NE transmission in prefrontal cortex,
showed that clonidine signicantly reduced PCP-induced decits
in spatial working memory (Marrs et al., 2005). In addition,
clonidine attenuated the ability of PCP to increase prefrontal
cortical dopamine release in rats (Jentsch et al., 2008). These two
studies suggest that clonidine can modulate PCP-induced changes
in catecholaminergic signaling.
499
In PWS on steady medication, studied in a double blind
manner, clonidine, at a number of doses, signicantly increased
PPI such that it no longer differed from that of healthy controls
(Oranje and Glenthoj, 2013a). Likewise, these researchers found
that clonidine, at the same doses as in the previous study,
normalized levels of P50 gating, where such gating is thought to
be a neural correlate of PPI decits (Oranje and Glenthoj, 2013b).
In healthy subjects, clonidine reduced acoustic startle amplitude
without affecting PPI, based on eyeblink behavior (Abduljawad
et al., 1997). In rats, stimulation of the NE releasing brainstem
nucleus, the locus coeruleus, produced decits in PPI that were
blocked by clonidine, as well as by the alpha1 adrenoceptor
antagonist drug prazosin (Alsene and Bakshi, 2011). Clonidine also
prevented PPI disruption by the alpha1 agonist cirazoline in rats,
but clonidine did not rescue PPI disruption by amphetamine and
actually increased PPI disruption produced by PCP (Swerdlow
et al., 2006). These studies suggest that clonidine may have
benecial effects on PPI, at least under some conditions, in both
humans and animal models.
Administration of the alpha2 adrenergic antagonist, yohimbine,
to rats did not alter startle baseline or PPI (Davis, 1988). Also in rats,
yohimbine reduced PPI without affecting startle amplitude, and
there was a trend toward clonidine attenuating this PPI disruption
(Powell et al., 2005). In summary, many of the alpha2 agonist
studies of clonidine or guanfacine suggest that these drugs could be
benecial in schizophrenia and merit further investigation.
5. Alpha1 adrenoceptor drug studies
The alpha1 adrenoceptor antagonist drug, prazosin, may exhibit
benecial effects on PPI. In rats, the alpha1 agonist drug cirazoline
disrupted PPI, and this effect was blocked by prazosin (Carasso
et al., 1998). Systemically administered prazosin also blocked the
decits in PPI produced by intracranial administration of the NMDA
receptor antagonist, MK-801 (Bakshi and Geyer, 1999). In neonatal
ventral hippocampus lesioned rats, which are thought to model
post-pubertal emergence of schizophrenia, PPI decits in the
lesioned rats were reversed by prazosin, without this drug having
a signicant effect on PPI in sham rats (Kamath et al., 2008). In
assessing the psychotomimetic properties of amphetamine in rats,
PPI decits produced by this drug were reversed by prazosin, but
not the beta adrenoceptor blocker drug, timolol (Alsene et al., 2010).
Likewise, prazosin blocked reductions in PPI produced by PCP, but
not those produced by the dopaminergic receptor agonist, apomor-
phine (Bakshi and Geyer, 1997). In contrast to the favorable effects
of prazosin on PPI in animal models, double blind, placebo
controlled administration to PWS had no effect on depression or
psychosis measures (Hommer et al., 1984).
On an electrophysiological level, prazosin dose-dependently
decreased burst ring and regularized ring patterns of dopami-
nergic neurons in the ventral tegmental area, while not affecting
their ring rate (Grenhoff and Svensson, 1993). Clonidine blocked
increases in rat prefrontal dopamine utilization induced by delta9-
tetrahydrocannabinol (THC) or PCP, and prazosin also blocked this
effect of PCP (Jentsch et al., 1998). In summary, the alpha1
antagonist drug, prazosin, was benecial in a number of rat studies
of impaired PPI.
6. Propranolol and other beta blocker studies
The brain penetrating, nonselective beta adrenoceptor blocker,
propranolol, may produce therapeutic effects in schizophrenia.
Treatment of PWS with another beta blocker, oxprenolol, produced
improvement in psychosis and in tardive dyskinesia
500 P.J. Fitzgerald / Psychiatry Research 215 (2014) 497504
symptomatology (Karniol and Portela, 1982). In 14 PWS who had
not responded to phenothiazine drugs, six completely remitted
when given propranolol, seven improved minimally to markedly,
and one had a severe toxic reaction to the drug (Yorkston et al.,
1974). In 55 PWS given propranolol, 26 were reported to have full
remission of symptoms, at least temporarily, with persons who had
been ill for less than a year having better results on this drug than
those who had been ill longer (Yorkston et al., 1976). A placebo
controlled assessment of supplementation of chlorpromazine treat-
ment with propranolol, found that both the placebo and the
propranolol groups improved, but the latter group improved
signicantly more (Yorkston et al., 1977).
A series of double blind studies found mixed results on
symptomatology in PWS. In 12 PWS who received adjunctive
propranolol or placebo treatment, propranolol was superior in
the overall group of persons, although three deteriorated
(Lindstrom and Persson, 1980). In contrast, a report involving only
ve PWS found no signicant improvement with propranolol
administration (King et al., 1980), as did a study of inpatient
PWS (Peet et al., 1981). Adjunctive propranolol given for unre-
mitted schizophrenia was, however, more effective than placebo
(Pugh et al., 1983). Consistent with propranolol having signicant
therapeutic effects, comparison with treatment by the antipsycho-
tic drug, thioridazine, found propranolol to be superior to this
drug, with improvement in both positive and negative symptoms
on propranolol (Eccleston et al., 1985). Propranolol was also
superior to placebo in maintaining improvement in symptomatol-
ogy rst produced by haloperidol (Manchanda and Hirsch, 1986).
In spite of the encouraging results of many of these older studies of
propranolol, a systematic review of randomized, placebo controlled
studies conducted prior to 2000, found that ve schizophrenia studies
of adjunctive treatment that combined conventional antipsychotics
with beta blockers lacked evidence for efcacy of the latter drugs
(Wahlbeck et al., 2000).
In a rat model of schizophrenia in which the amphetamine-like
drug, phenylethylamine (PEA), induces stereotyped behavior, this
effect was blocked by the alpha adrenoceptor blockers, phentola-
mine and phenoxybenzamine, but not by propranolol (Borison and
Diamond, 1978). Also in rats, the serotonin 5-HT1B receptor
agonist drug, RU 24969, potently disrupted PPI, and this was
prevented by propranolol (Sipes and Geyer, 1994). In summary,
propranolol showed benets (and in some cases, toxicity or
negative effects) in a number of clinical studies, some of which
were randomized, placebo controlled studies.
7. Bipolar disorder studies
Schildkraut (1965) put forth the hypothesis that the catecho-
lamines, including NE and dopamine, are involved in the etiology
of bipolar disorder, with elevated levels during states of mania.
Consistent with this idea, in a study that included two rapidly
cycling persons with bipolar disorder, their plasma MHPG levels
were higher during mania than during depression (Jimerson et al.,
1981). Acutely manic subjects have also been demonstrated to
exhibit elevated CSF MHPG compared with healthy controls
(Swann et al., 1983). Recently, an association was found between
polymorphisms of the dopamine beta-hydroxylase gene (respon-
sible for biosynthesis of NE) and bipolar disorder in Turkish
persons (Ates et al., 2013). Studies are reviewed below indicating
that bipolar disorder and schizophrenia have overlapping char-
acteristics, consistent with the idea elevated NE is a shared
etiological factor in the two disorders.
The classical Kraepelinian view of schizophrenia and bipolar
disorder is that they are discrete entities, but there is evidence that
they actually exist as a continuum relative to each other (Taylor,
1992). Schizophrenia and bipolar disorder may be transmitted
independently; however, schizophrenia probands had elevated
familial association with unipolar depression and with schizoaf-
fective disorder-unipolar type (Maier et al., 1993). Data from
monozygotic and dizygotic twins with schizophrenia or bipolar
disorder suggest that the two disorders have overlapping genetics
(Cardno et al., 2002). An analysis of single nucleotide polymorph-
isms in parent-offspring trios concluded that there are a number
of genes previously associated with schizophrenia, including
disrupted-in-schizophrenia 1 (DISC1), that may also contribute to
bipolar disorder (Perlis et al., 2008). A meta-analysis concluded
that rst degree relatives of probands with schizophrenia have
signicantly elevated rates of bipolar disorder relative to controls,
and rst degree relatives of probands with bipolar disorder have
marginally signicantly elevated rates of schizophrenia (Van
Snellenberg and de Candia, 2009).
A group of adults with bipolar disorder who were acutely
psychotically manic, exhibited impaired PPI relative to control
subjects, and did not differ from PWS in PPI (Perry et al., 2001).
However, a sample of children with bipolar disorder, who were
neither manic nor psychotic, did not exhibit impaired PPI relative
to controls (Rich et al., 2005). Also, in euthymic adults with bipolar
disorder, PPI was not impaired (Barrett et al., 2005). Likewise, a
comparison of persons with bipolar disorder who were in a manic
or mixed mood, versus healthy controls, found no evidence of
reduced PPI, which the authors attributed to the low incidence of
psychosis in their subjects (Carroll et al., 2007). However, a more
recent study found that remitted persons with bipolar disorder, as
well as their unaffected siblings, had impaired PPI relative to
healthy controls (Giakoumaki et al., 2007).
In summary, multiple lines of evidence suggest functional overlap
between bipolar disorder and schizophrenia: they run together in
families and may share various alleles; existence of schizoaffective
disorder further suggests overlapping factors in the two diseases;
they share symptomatology such as paranoia, hallucinations, and
delusions; they have overlapping drug treatments; and they may
share impaired PPI. Therefore, the two diseases may share etiological
factors, including elevated noradrenergic signaling.
8. Hypertension studies
Elevated noradrenergic signaling is associated with hyperten-
sion (Solt et al., 1990; Tycinska et al., 2011), and drugs such as
clonidine that modulate release of NE can lower blood pressure
(Onesti et al., 1971). PWS are at risk for developing hypertension,
partly because use of antipsychotic medications can produce
adverse metabolic side effects (Newcomer, 2006). Data from a
large multisite study in the United States, called Clinical Anti-
psychotic Trials of Intervention Effectiveness (CATIE), found that
20 percent of PWS had hypertension (Chwastiak et al., 2006). PWS
or schizoaffective disorder, who had comorbid alcohol use dis-
orders, collectively had a very high rate of hypertension, 43
percent (Batki et al., 2009). Analysis of data based on United
States hospital discharges, which included over 26,000 PWS and
1.9 million control subjects, found elevated rates of essential
hypertension (proportional morbidity ratio (PMR) 1.2) in the
disease (Weber et al., 2009). PWS who also had hypertension
showed decits in recognition memory, whereas control subjects
did not (Friedman et al., 2010). South Carolina Medicaid program
data from PWS who were newly prescribed an antipsychotic
medication, found that 15.6 percent had hypertension at study
onset and 41.8 percent did spanning 3 years of use, suggesting these
drugs have a large effect on development of hypertension (Jerrell
et al., 2010). In summary, many PWS exhibit hypertension and it is
unclear to what extent this is caused solely by use of antipsychotic
 P.J. Fitzgerald / Psychiatry Research 215 (2014) 497504 501

medications. Future studies that measure blood pressure prior to pheochromocytoma-induced psychosis, although other signaling
administration of these drugs, in comparison with unmedicated molecules may instead be the cause.
control subjects, would further address this issue. At a molecular level, the AKT/GSK3 signaling pathway has been
implicated in schizophrenia (Emamian, 2012). Mice with gene
targeted knockin of GSK3, which made this molecule insensitive to
PKB/SGK-mediated inhibition, had a signicantly higher level of
9. Psychological stress studies
plasma NE and higher blood pressure than wild type mice
(Siraskar et al., 2011). This mouse study may suggest that the
NE is one of the principal molecules released in the brain and
AKT/GSK3 signaling pathway interacts with schizophrenia through
bloodstream in response to psychological stress, thereby helping
noradrenergic mechanisms.
mediate the so-called ght-or-ight response (Dienstbier, 1989).
Animal studies also suggest that NE is released in the brain after
exposure to acute stress (Hajos-Korcsok et al., 2003). PWS exhibit
11. Discussion
abnormal sensitivity to psychological stress and this may not be a
consequence of cognitive impairment (Myin-Germeys et al., 2002).
The above data are in many cases consistent with the hypoth-
PWS also experience greater amounts of stress in their daily lives
esis elevated noradrenergic signaling is an etiological factor in at
than healthy subjects, including sources related to domestic envir-
least some cases of schizophrenia. This hypothesis is not suggest-
onment and depression (Betensky et al., 2008). In persons at ultra-
ing that elevated NE is the only factor in schizophrenia, just that it
high risk for developing psychosis, psychological stress was a
may be an important, additional one. Additional double blind,
signicant predictor for exhibiting more severe positive symptoms
placebo controlled studies of adjunctive or exclusive treatment of
(Pruessner et al., 2011). A group of community dwelling PWS had
schizophrenia with NE transmission altering drugs, such as cloni-
experienced signicantly more traumatic events before age 17 than
dine and propranolol, would be highly informative to further
control subjects, and a high level of exposure to trauma through the
evaluate this hypothesis and its potentially immediate clinical
lifespan was associated with non-remission of positive symptoms
implications. Additional genetic studies may also further implicate
(Cohen et al., 2012). In adolescents with schizophrenia, ongoing
the noradrenergic system in schizophrenia.
symptom severity positively correlated with exposure to psycholo-
Some of the above data suggest improvement in executive
gical stress (Lee and Schepp, 2009). Healthy subjects, who were
functions such as working memory with noradrenergic drugs such
exposed to a stressor consisting of environmental noise and being
as alpha2 agonists, where working memory may be impaired in
asked difcult knowledge questions, exhibited an increase in
schizophrenia. The parsimonious interpretation may be that
paranoia, depression, and negative emotion (Lincoln et al., 2009).
alpha2 agonists (opposite for alpha2 antagonists) are producing
Indian PWS who were exposed to signicant stressors, such as
a net decrease in NE transmission, since they lower the synaptic
unemployment, exhibited greater rates of relapse (Chabungbam
concentration of NE (van Gaalen et al., 1997) for all adrenoceptors
et al., 2007). These studies suggest that a history of exposure to
but agonize only a single subtype of postsynaptic adrenoceptor,
trauma or other signicant stressors, as well as ongoing stressors,
alpha2 (possibly alpha2A in particular, Franowicz et al., 2002).
may play a role in the manifestation of schizophrenia.
Also, postsynaptic alpha2 receptors may be functionally opposed
Rat pups exposed to a brief, 24 h period of maternal deprivation a
to other adrenoceptors, especially considering that presynaptic
few days after birth, exhibited decits in PPI when tested as adults
alpha2 receptors are inhibitory autoreceptors (Fitzgerald, 2011).
(Ellenbroek et al., 1998). A related study, which unlike the previous
Nonetheless, our current knowledge of alpha2 pharmacological
study, used rat subjects that were offspring of different dams, found
agents suggests that it is an oversimplication, and possibly an
that perinatal, 24 h maternal separation did not disrupt PPI in
incorrect one, to conclude that these drugs may be therapeutic for
adulthood (Lehmann et al., 2000). A mouse strain comparison report,
schizophrenia by decreasing noradrenergic transmission. Instead,
which also examined maternal separation, but for 3 h a day for the
these agents may be producing their therapeutic effects by
rst 2 weeks of life, also found no decits in PPI for the ve strains for
activating postsynaptic alpha2 receptors.
which there were data (Millstein et al., 2006). In contrast, exposure to
Oranje and Glenthoj have recently suggested that clonidine
prenatal stress, in which the pregnant rat mother was subjected to
produces therapeutic effects on PPI and P50 gating in PWS (Oranje
chronic mild stress, found strongly impaired PPI in adult offspring
and Glenthoj, 2013a, 2013b). They suggest that this drug may do so
(Kjaer et al., 2010). These data suggest that either prenatal or early life
by altering noradrenergic signaling in the locus coeruleus or the
exposure to signicant stress may, under some conditions, disrupt PPI
prefrontal cortex, although it is not clear that clonidine achieves its
later in life in rodent models.
therapeutic effect simply by decreasing presynaptic release of NE.
In summary, psychological stress may help cause or worsen
Oranje and Glenthoj also note that alpha1 adrenoceptors play a
schizophrenia, but the effects of the illness itself causing stress in
role in PPI decits.
the individual need to be disentangled, including when the illness
Arnsten (2004) notes that NE may indeed play an important
is in a prodromal state. Also, stress hormones other than NE, such
role in prefrontally mediated cognitive functioning in schizophre-
as epinephrine and cortisol, may be playing a role in
nia. That paper suggests that modest levels of NE release are
schizophrenia.
cognitively benecial through activation of postsynaptic alpha2a
receptors in prefrontal cortex. However, high levels of NE release
during exposure to psychological stress are detrimental to execu-
10. Additional data tive functioning, both through activation of the molecular protein
kinase C pathway and the alpha1 receptor (and possibly the beta1
There is a case report of a Kenyan woman who experienced receptor (Ramos and Arnsten, 2007)). Thus, use of particular types
psychosis while apparently suffering from pheochromocytoma, of noradrenergic pharmacological agents may have benecial
which is a tumor of the adrenal glands that excretes elevated effects on cognition in PWS (Arnsten, 2004). Regarding this latter
amounts of catecholamines, including NE (Bahemuka, 1983). Soon point, the alpha2a agonist drug, guanfacine, is effective in treating
after surgery to remove the tumor, her catecholamine levels a variety of prefrontally mediated cognitive disorders, such as
dropped and her psychosis remitted (Bahemuka, 1983). This study Tourette0 s syndrome and attention decit hyperactivity disorder
suggests that elevated NE may play a role in this case of (Arnsten, 2009; Arnsten and Jin, 2012). Guanfacine may achieve its
502 P.J. Fitzgerald / Psychiatry Research 215 (2014) 497504
therapeutic effects on cognition in part by modulating dendritic
spine inputs to deep layer III pyramidal cells in prefrontal cortex
(Arnsten, 2011).
In some more recent publications, Arnsten and colleagues have
suggested that beta adrenoceptors also play a key role in prefron-
tally mediated working memory functions, which could be
impaired by psychological stress and neuropsychiatric disorders
such as schizophrenia (Ramos and Arnsten, 2007). These research-
ers showed that the selective beta1 antagonist drug, betaxolol,
improved working memory performance in rats and monkeys
(Ramos et al., 2005). More recently Arnsten and colleagues showed
that the beta2 agonist drug, clenbuterol, also enhanced working
memory performance in rats and monkeys (Ramos et al., 2008).
These two studies on beta adrenoceptors suggest that beta1 and
beta2 receptors may have functionally opposing roles in working
memory. Future studies on receptor subtype-selective beta adreno-
ceptor agents, both in animal models and humans, would shed
further light on the roles of these receptors in cognition, as well as
in neuropsychiatric disorders such as schizophrenia.
A recent study suggested that medial prefrontal cortex in
particular may facilitate behavioral control in both rodents and
humans in part by modulating low frequency oscillations between
this brain region and motor cortex (Narayanan et al., 2013).
One interesting possibility is that in schizophrenia, the phe-
nomenon of paranoia (and possibly, the positive signs in general)
may be particularly related to elevated NE. Also, elevated nora-
drenergic signaling may help produce paranoia in other neurop-
sychiatric diseases, including bipolar disorder or psychotic
unipolar depression. Aside from a specic role in producing
paranoia, elevated noradrenergic signaling may extend to the
etiology of schizoaffective disorder and schizophrenia-related
personality disorders such as schizotypal and schizoid disorders.
Alcohol use disorders and schizophrenia are frequently comor-
bid (Jones et al., 2011), where both types of disorders may be
partially based in elevated noradrenergic signaling (Fitzgerald,
2012). Perhaps elevated noradrenergic signaling is a shared factor
in the comorbidity of a number of psychiatric disorders.
The most important implication of this paper is that noradre-
nergic transmission altering pharmacological agents may be con-
sidered as a second line treatment of schizophrenia, when standard
antipsychotic drug treatments show only a partial response, have
unacceptable side effects such as tardive dyskinesia, or simply fail
outright. In this scenario, selective NE altering agents such as
clonidine, propranolol, or prazosin may be added to a given
person0 s antipsychotic drug regimen, or be used as an alternative
if that regimen has failed, although if so these persons should be
monitored carefully for signs of deterioration (Yorkston et al., 1974;
Lindstrom and Persson, 1980). It should be noted, however, that
antipsychotic drugs such as chlorpromazine already have noradre-
nergic transmission modulating properties, including via the alpha1
adrenoceptor (Amargos-Bosch et al., 2003). It should also be noted
that beta blockers such as propranolol may be associated with
alterations in the cardiac QT interval, as well as potential increases
in fatigue or sexual dysfunction (Milne et al., 1980; Ko et al., 2002).
However, it is not clear that beta blocker therapy is associated with
induction of major depression (Ko et al., 2002; Steffensmeier et al.,
2006). Nonetheless, a number of studies listed above suggest that
noradrenergic transmission altering agents may be particularly
helpful as adjunctive treatment for the paranoid subtype of schizo-
phrenia, or when positive symptoms are particularly prominent, but
may also be helpful for negative signs (Eccleston et al., 1985).
Conicts of interest statement
None declared.
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