Review articleIs elevated norepinephrine an etiological factor in some cases of schizophrenia?
Introduction
Identification of the precise etiological factors responsible for schizophrenia remains a widely debated topic. Dating back a number of decades, a variety of biological theories have been put forth to explain this severe neuropsychiatric disorder. These theories include the widely known and intensely debated “dopamine hypothesis of schizophrenia”, where both elevated and decreased dopamine transmission have been posited (Carlsson, 1977, Grace, 1991, Carlsson et al., 1997, Carlsson and Carlsson, 2006). A more recent, widely studied theory suggests that hypofunction of the glutamatergic NMDA receptor is a prominent causative factor in the disease (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, predisposing 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 widespread 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 identification of potential additional factors may result in improvement in treatment, through use of pharmaceuticals and other methods.
This paper puts forth the hypothesis that elevated noradrenergic 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 hypothesis does not contradict the theories mentioned above, such as the dopamine hypothesis or the NMDA receptor hypofunction hypothesis, 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 NE's postsynaptic receptor populations, is an etiological factor in some cases of schizophrenia.
If elevated NE is an etiological factor in some cases of schizophrenia, 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 individual's life, although psychological 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 identified, one possibility is that it involves dysregulated signaling in prefrontal cortex (Robbins, 2005, Arnsten, 2011). Executive functional alterations, 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 modulation of alpha1 and alpha2 adrenergic receptors can alter working 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 briefly 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 fluid+concentration, (2) desipramine/“tricyclic antidepressant(s)”/clonidine/guanfacine/yohimbine/prazosin/“beta blocker(s)”/propranolol, (3) pheochromocytoma, (4) “bipolar disorder”+proband(s), (5) hypertension+comorbidity, and (6) “psychological stress”+comorbidity. 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.
Section snippets
Norepinephrine and metabolite level studies
Blood and cerebrospinal fluid (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
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 beneficial effects on both mood and residual psychoticism in recovering PWS (
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, crossover 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
Alpha1 adrenoceptor drug studies
The alpha1 adrenoceptor antagonist drug, prazosin, may exhibit beneficial 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 deficits 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
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 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
Bipolar disorder studies
Schildkraut (1965) put forth the hypothesis that the catecholamines, 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
Hypertension studies
Elevated noradrenergic signaling is associated with hypertension (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 Antipsychotic Trials of Intervention Effectiveness (CATIE),
Psychological stress studies
NE is one of the principal molecules released in the brain and bloodstream in response to psychological stress, thereby helping mediate the so-called “fight-or-flight” 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 abnormal sensitivity to psychological stress and this may not be a consequence of cognitive impairment (Myin-Germeys et al., 2002). PWS also experience greater amounts
Additional data
There is a case report of a Kenyan woman who experienced psychosis while apparently suffering from pheochromocytoma, which is a tumor of the adrenal glands that excretes elevated amounts of catecholamines, including NE (Bahemuka, 1983). Soon after surgery to remove the tumor, her catecholamine levels dropped and her psychosis remitted (Bahemuka, 1983). This study suggests that elevated NE may play a role in this case of pheochromocytoma-induced psychosis, although other signaling molecules may
Discussion
The above data are in many cases consistent with the hypothesis elevated noradrenergic signaling is an etiological factor in at least some cases of schizophrenia. This hypothesis is not suggesting that elevated NE is the only factor in schizophrenia, just that it may be an important, additional one. Additional double blind, placebo controlled studies of adjunctive or exclusive treatment of schizophrenia with NE transmission altering drugs, such as clonidine and propranolol, would be highly
Conflicts of interest statement
None declared.
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Spared performance but increased uncertainty in schizophrenia: Evidence from a probabilistic decision-making task
2022, Schizophrenia ResearchCitation Excerpt :The findings thus corroborate hypotheses of aberrant norepinephrinergic signaling in schizophrenia (Fitzgerald, 2014; Mäki-Marttunen et al., 2020) and call for further investigation of the different implicated neuromodulatory systems and their interactions. Accumulated evidence from this field could inspire the development of psychopharmacological treatments where adding norepinephrine transmission modulating agents might show beneficial effects in subgroups of patients (Fitzgerald, 2014). Furthermore, the study highlights the role of uncertainty processing in schizophrenia, a concept that is already addressed in metacognitive training interventions (Moritz and Woodward, 2007).
Association of working memory and elevated overnight urinary norepinephrine in patients with schizophrenia
2021, Journal of Psychiatric ResearchCitation Excerpt :Additionally, age, gender and some psychotropic medications can have a significant effect on norepinephrine, but after controlling for these variables, the relationship between norepinephrine and working memory remained significant, suggesting that the relationship may not be entirely influenced by these factors. In conclusion, this study replicated the finding of elevated peripheral norepinephrine levels in schizophrenia Pscheidt et al. (1964); Kemali et al. (1982); Barbeito et al. (1984); Breier et al. (1990), provided new evidence that working memory deficits in schizophrenia is significantly associated with elevated overnight urinary norepinephrine levels, and yielded clinical empirical evidence to support the hypothesis that psychosis severity is related to elevated norepinephrine (Fitzgerald, 2014). Further investigation of the mechanisms of the peripheral origin of norepinephrine and its relationship to cognition may provide a possible strategy to identify more effective treatments for some patients whose psychosis and working memory deficits are not responsive to currently available antipsychotic medications.
Association between genetic variants of the norepinephrine transporter gene (SLC6A2) and bipolar I disorder
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryThe role of norepinephrine in the pathophysiology of schizophrenia
2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The evidence led them to conclude that the positive symptoms are consistent with a hyperactivity of NE system, while negative symptoms are consistent with a hypoactivity of NE system. In addition, therapeutic effects of certain NE-receptor agonists (such as alpha-2 receptor agonists) have been observed in several studies (for a review see Fitzgerald, 2014), including improvement in positive and cognitive symptoms, as well as in reflexive neurophysiological processes known to be disrupted in SCZ, such as pre-pulse inhibition (PPI) or P50 gating. Studies using antidepressants such as serotonin and NE reuptake inhibitors (SNRIs), suggest that they may have a small but positive effect on cognitive symptoms (Chamberlain and Robbins, 2013; Soczynska et al., 2014; Vernon et al., 2014).
No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals
2018, Psychiatry ResearchCitation Excerpt :A number of studies have found concentrations of noradrenaline to be altered in serum and plasma in people with schizophrenia and to correlate with the severity of symptoms in these patients. Some studies have also shown that substances affecting noradrenaline signaling, such as clonidine, can have a therapeutic effect on symptoms of schizophrenia (Bjerkenstedt et al., 1985; Fitzgerald, 2014). The major metabolites of dopamine, serotonin and noradrenaline are homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively.