Posted 22 September 2012 - 02:35 PM
Copy and paste for now......Cognition and depression: the effects of fluvoxamine, a sigma-1receptor agonist, reconsidered
Ian Hindmarch1* and Kenji Hashimoto2
1Emeritus Professor, University of Surrey, Guildford, UK
2Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan
Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural
atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant countertherapeutic
cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of
some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy
and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/
reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis,
depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In
humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the
mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine
may help improve cognitive outcomes in patients with depression. Copyright # 2010 John Wiley & Sons, Ltd.
key words—cognition; depression; fluvoxamine; neurogenesis; sigma-1 receptor
INTRODUCTION
Major depressive disorder (MDD) is the most common
and widespread of all psychiatric disorders; it has a
lifetime prevalence of 16.2%, a 12-month prevalence
of 6.6% in developed countries (Trivedi et al., 2007)
and is a leading cause of disability worldwide (WHO,
2008). The significant unmet therapeutic need in MDD
is evidenced by increased levels of mortality and
morbidity and reduced quality of life in patients with
depression and up to 850 000 cases of suicide per
annum (WHO, 2008).
Good cognitive function is fundamental to psychological
well-being and for dealing with perceived
stresses. Cognitive impairment is a ubiquitous and
characteristic feature of patients suffering from MDD
(Widlo¨cher, 1983) and causes not only aberrant coping
with stress, a prime aetiological factor in the development
of depression, but also reduced brain metabolism
and neural atrophy, particularly in the hippocampus,
amygdala and prefrontal cortex. These problemsmay be
symptoms of depressive illness and persist (as residual
symptoms) despite otherwise effective antidepressant
therapy. They may also, however, emerge as adverse
effects of some antidepressants (Fava, 2003). Residual
symptoms (including anxiety, sleep disturbance, somnolence/
fatigue and apathy) are common in individuals
treated for MDD and they are associated with an
increased risk of relapse and poor psychosocial
functioning (Fava, 2006).
The first principle of pharmacotherapy is to ‘do no
harm’ and it is particularly important that antidepressant
therapy should cause no further cognitive impairment
in patients with depression. This is especially so
for elderly patients or those with an already reduced
cognitive ability and also those patients where an intact
cognitive function is an essential prerequisite for safe
or optimal everyday functioning, e.g. students, car
drivers, machine operators, etc.
This paper considers the role and mechanisms of the
sigma-1 receptor in facilitating cognition and promoting
neurogenesis and examines the potential for sigma-1
receptor agonists, e.g. fluvoxamine, to improve cognitive
outcomes in patients with depression.
human psychopharmacology
Hum. Psychopharmacol Clin Exp 2010; 25: 193–200.
Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/hup.1106
* Correspondence to: I. Hindmarch, Emeritus Professor, University of
Surrey, Guildford GU2 7XH, UK. Tel: þ44(0)1304853992; Fax:
þ44(0)1304852992 E-mail: ian@psychopharma.co.uk
Copyright # 2010 John Wiley & Sons, Ltd.
Received 22 December 2009
Accepted 1 February 2010
A Medline search for peer-reviewed publications was
conducted from 1975 to August 2008 using the keywords
and subjects ‘depression’, ‘MDD’, ‘cognition’, ‘cognitive’,
‘fluvoxamine’, ‘SSRI’, ‘impairment’, ‘neurogenesis’,
‘sigma’ and ‘antidepressant’. Further articles were
found using the reference citations from articles identified
in the Medline search.
COGNITION, DEPRESSION AND
STRUCTURAL CHANGES IN THE BRAIN
Cognitive impairment broadly disrupts human behaviour
and functioning and is both a cause and a symptom
of depressive illness. Cognitive impairment is manifest
in many ways in patients with MDD, including
psychomotor retardation, memory loss, confused
thought, impaired judgement, increased fear and
psychotic thought, risky decision making and reduced
learning competence (Silva and Larach, 2000; Porter
et al., 2003; Campbell and Macqueen, 2004; Elderkin-
Thompson et al., 2004; DeLuca et al., 2005; Thomas
et al., 2008). In some individualswith a history ofMDD,
cognitive deficits (notably problem solving difficulties)
also appear to be linked to suicidality (Crane et al.,
2007).
It has long been hypothesised that the cognitive
structures which enable the individual to represent the
environment have a neuroanatomical underpinning
(Sherwood et al., 2008). Whilst exposure to acute
everyday stress can facilitate memory formation and
consolidation, chronic stress and anxiety impairs
cognitive performance (Reagan et al., 2008). Furthermore,
‘depressogenic cognitions’ are activated by
chronic distress in MDD subjects, leading to stress
exacerbation, anxiety and a poorer treatment outcome
(Candrian et al., 2007).
It is now believed that chronic stress may elicit
neurochemical, neuroanatomical and cellular changes
that may have deleterious consequences on higher brain
functioning. Significant neurobiological consequences
involving structural, functional and molecular alterations
occur in several areas of the brain, particularly
in the hippocampus, amygdala and prefrontal cortex
during depression (Bremner, 1999; Sapolsky, 2001;
Maletic et al., 2007).
Atrophy of the human hippocampus is seen in a
variety of psychiatric and neurological disorders such as
recurrent depression, schizophrenia, bipolar disorder,
post-traumatic stress disorder, epilepsy, head injury and
Alzheimer’s disease. Several studies using volumetric
magnetic resonance imaging have found decreases in
left hippocampal volumes (Bremner et al., 2000;
Mervaala et al., 2000; Frodl et al., 2002; Vythilingam
et al., 2002), right hippocampal volumes (Steffens et al.,
2000) and total hippocampal volumes (Sheline et al.,
1999;MacQueen et al., 2003; Dhikav and Anand, 2007)
in patients with depressive illness. Decreases in
hippocampal volume were associated with deficits in
hippocampal-dependentmeasures of cognitive function.
Imaging studies have revealed that the amygdala is a
further site for neuroanatomical alterations in depressive
illness (McEwen, 2003; Reagan et al., 2008).
Over a 3-year prospective study period, MDD
patients showed significant grey matter density
reductions within hippocampus, anterior cingulum,
left amygdala and right dorsomedial prefrontal cortex
compared with controls. Patients who experienced
stable remission during this period had less volume
decline than non-remitted patients in the left hippocampus,
left anterior cingulum, left dorsomedial
prefrontal cortex, and bilaterally in the dorsolateral
prefrontal cortex (Frodl et al., 2008).
BEHAVIOURAL TOXICITY OF
ANTIDEPRESSANTS
Clinical remission of the symptoms of depression is
influenced by the degree of integrity of the cognitive
system. It is therefore important that the drugs used to
treat depression are free from untoward effects on
cognitive and psychomotor competence.
Antidepressant agents can be broadly classified
according to the extent to which they impair cognitive
function because of their intrinsic pharmacological
activity. This, so-called, behavioural toxicity (Hindmarch
et al., 1990) is independent of the class of drug and
differences exist between antidepressants irrespective of
their attributed therapeutic class. As regards behavioural
toxicity, antidepressants can be sedative, excitatory or
neutral (Spring et al., 1992; Hindmarch, 1995;Wadsworth
et al., 2005).
The broad receptor binding spectrum of antidepressants
confers specific secondary pharmacodynamic
properties and adverse behavioural effects. For example,
paroxetine (selective serotonin reuptake inhibitor; SSRI)
has significant anticholinergic properties and appreciable
affinity for the noradrenaline transporter. Anticholinergic
activity can lead to clinically significant
cognitive impairment including forgetting, confusion
and problems with concentration (Stein and Strickland,
1998; Ridout et al., 2003). A disruption of memory
caused by paroxetine was evident in a clinical trial
(Schmitt et al., 2001) where memory recall was
impaired after 7 days of treatment at 20 mg/day.
Cognitive and psychomotor impairment may occur
regardless of the class of antidepressant. In a retro-
Copyright # 2010 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2010; 25: 193–200.
DOI: 10.1002/hup
194 i. hindmarch and k. hashimoto
spective study of 2428 nursing home residents there was
little difference in rates of falls between those treated
with tricyclic antidepressants and those treated with the
SSRI sertraline (Thapa et al., 1998).
The secondary binding profile of the SSRI fluvoxamine
includes potent agonist activity at sigma-1
receptors (Narita et al., 1996; Hashimoto, 2009). This
may be of potential clinical significance as the (largely
preclinical) evidence suggests that sigma-1 agonist
activity may help reverse deleterious effects on brain
function and cognitive faculties (Monnet, 2005;
Hashimoto, 2009) and improve cognitive impairments
in a patient with schizophrenia (Iyo et al., 2008).
CLINICAL SIGNIFICANCE OF SIGMA
RECEPTORS
Sigma receptors, discovered in 1976 (Martin et al.,
1976), have a unique pharmacological profile (Su and
Hayashi, 2003) and are located in the cell membrane,
although they are also dynamic endoplasmic reticulum
(ER) proteins thought to affect intracellular second
messenger systems, particularly calcium mobilisation.
Sigma-1 receptors are found mainly in regions of the
cerebellum, cingulate nucleus, hippocampus, hypothalamus
and pones (Stahl, 2005). A recent study by Hayashi
and Su (2007) identified the sigma-1 receptor as a novel
ER chaperone. Sigma-1 receptors are predominantly
expressed at the mitochondrial-associated ER membrane,
thereby regulating the IP3 receptor-mediated
Ca2þ influx from the ER to the mitochondria (Hayashi
and Su, 2007). Because mitochondrial Ca2þ originating
fromthe ER is a key activator of three dehydrogenases in
the tricyclic acid (TCA) cycle, the sigma-1 receptors are
assumed to serve as a regulator of ATP production and
bioenergetics within the cell (Hayashi and Stahl, 2009).
Sigma-1 receptors have been shown to regulate a
number of neurotransmitter systems, including the
glutamatergic, dopaminergic, serotonergic, noradrenergic,
and cholinergic systems. Glutamate modulation
has the effect of promoting neurogenesis via nerve
growth factor which initiated adaptive neural plasticity
as a protection or reaction to stress (Takebayashi et al.,
2002; Nishimura et al., 2008). The accumulated
evidence also suggests that the activation/up regulation
of sigma-1 receptors promotes neuronal differentiation
as well as a robust anti-apoptotic action (Hayashi and
Su, 2008). As reviewed by Stahl (2005), sigma-1
receptor ligands have been linked to the improvement
of memory and learning processes (Debonnel and de
Montigny, 1996; John et al., 1997; Waterhouse et al.,
1997; Takebayashi et al., 2002; Guitart et al., 2004;
Hashimoto et al., 2007), depression (Senda et al., 1996;
Phan et al., 2002; Urani et al., 2002;Wang et al., 2003;
Ishikawa and Hashimoto, 2010), anxiety (Ucar et al.,
2002; Ishikawa and Hashimoto, 2010), psychosis
(Kamei et al., 1998; Urani et al., 2002; Ishikawa
and Hashimoto, 2010), stress (Bergeron and Debonnel,
1997; Maurice and Lockhart, 1997; Maurice et al.,
2001), aggression (Phan et al., 2002) and pharmacodependence
(Ucar et al., 1997; Maurice et al., 2001;
Phan et al., 2002).
The action of sigma-1 receptor agonists on the
function via NMDA receptors may be important as
another mechanism of enhancement of glutamatergic
function. It is known that sigma-1 receptor agonists do
not bind to the glycine site on the NMDA receptors
(located on post-synaptic neurons) because sigma-1
receptors located on the ER. However, it is well known
that sigma-1 receptors might play a role in the central
nervous system (CNS) as a modulator of signal
transduction in neurotransmitter systems such as
NMDA receptors (Hashimoto and Ishiwata, 2006).
Thus, it seems that sigma-1 receptors might have
important roles in glutamatergic function indirectly via
NMDA receptors.
Various sigma-ligands have been investigated over
the years for potential clinical applications. Preclinical
and clinical studies have encompassed, for example,
functional diarrhoea as a model of somatoform disorder
(involving igmesine [also known as JO, 1784], a potent
and selective ligand and one of the earliest tested
[Roman et al., 1990]), depression (igmesine, opipramol),
anxiety (opipramol, siramisine), schizophrenia
(panamasine, rimcazole) and somatoform disorders
(opipramol). In many cases, however, further development
of these agents was stopped for commercial
reasons (Volz and Stoll, 2004). Clinical investigations
into the potential sigma receptor-related effects of
fluvoxamine, however, continue.
FLUVOXAMINE
Several lines of evidence support the important role of
the sigma-1 receptor agonism in the mechanism of
action of fluvoxamine. Of a number of antidepressants
tested, fluvoxamine was a ligand and had the highest
affinity for the sigma-1 receptor in rat brain (Table 1;
Narita et al., 1996; Hayashi and Su, 2004; Hashimoto,
2009).
Consistent with these findings, high occupancy of
sigma-1 receptors has also been observed in living
human brain following the administration of therapeutic
doses of fluvoxamine (i.e. 50–200 mg) to 15 healthy
male volunteers. A single administration of fluvoxamine
(200 mg) but not paroxetine (20 mg)markedly decreased
Copyright # 2010 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2010; 25: 193–200.
DOI: 10.1002/hup
cognition and depression 195
the distribution volume of [11C]SA4503, a selective
positron emission tomography (PET) ligand for the
sigma-1 receptor in the brain (Figure 1). Also revealed
by dynamic PET, fluvoxamine significantly and dosedependently
bound to sigma-1 receptors in all brain
regions (i.e. frontal cortex, parietal cortex, occipital
cortex, head of the caudate nucleus, thalamus and
cerebellum). The dose-dependency also appeared to
occur at the temporal cortex, anterior cingulated gyrus
and putamen (correlation at these sites not statistically
significant) (Ishikawa et al., 2007).
The relatively high affinity of fluvoxamine for the
sigma-1 receptor may result in a variety of clinically
relevant activities and may explain the ameliorating
effects observed with fluvoxamine in animal models
of psychoses, depression, stress, anxiety, obsessivecompulsive
disorder (OCD), aggression, memory and
learning (Kamei et al., 1998; Maurice et al., 1999a,b;
Mamiya et al., 2000; Urani et al., 2001; Egashira
et al., 2007; Hashimoto et al., 2007).
Phencyclidine-induced cognitive deficits in mice were
significantly improved by sub-chronic (2-week) administration
of fluvoxamine (20 mg/kg b.w./day), but not
paroxetine (10mg/kg b.w./day) or sertraline (10 or 20 mg/
kg b.w./day) (Hashimoto et al., 2007; Ishima et al., 2009).
Co-administration of NE-100 (1mg/kg b.w./day) antagonised
the effect of fluvoxamine, suggesting that the
effects of fluvoxamine are mediated via agonistic activity
at sigma-1 receptors (Hashimoto et al., 2007).
Fluvoxamine, via sigma-1 receptor agonism, was found
to potentiate nerve-growth factor (NGF)-induced neurite
outgrowth in PC12 cells (Figure 2). The potentiation by
fluvoxamine was blocked by co-administration of the
selective sigma-1 receptor antagonist NE-100, suggesting
that sigma-1 agonists play a role in blocking the
enhancement of NGF-induced neurite outgrowth. Unlike
fluvoxamine, sertraline, which has a moderate affinity for
Table 1. In vitro affinity of various agents for rat sigma-1 binding sites
(Narita et al., 1996; Hayashi and Su, 2004)
Drug
Ki (nM)
Ki ratio
Sigma-1 Sigma-2 (sigma-2/sigma-1)
SSRIs
Fluvoxamine 36 8439 234
Sertraline 57 5297 93
S(þ)Fluoxetine 120 5480 46
()Fluoxetine 240 16 100 68
Citalopram 292 5410 19
Paroxetine 1893 22 870 12
Tricyclic antidepressants
Imipramine 343 2107 6
Desipramine 1987 11 430 6
Figure 1. High occupancy of sigma-1 receptors in human brain by fluvoxamine, but not paroxetine; shown are distribution volume images of [11C]SA4503-
PET before and after a single oral administration of each agent (reproduced with permission from Ishikawa et al., 2007)
Copyright # 2010 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2010; 25: 193–200.
DOI: 10.1002/hup
196 i. hindmarch and k. hashimoto
sigma-1 receptors, did not alter NGF-induced neurite
outgrowth. The reasons underlying this discrepancy
between these two agents are currently unclear, although
one possibility may involve the difference in pharmacological
actions (agonist vs. antagonist) between them at
sigma-1 receptors. Another possibility may be that other
pharmacological activities of sertralinemask the effects of
sigma-1 receptor agonism (Takebayashi et al., 2002;
Nishimura et al., 2008). These findings suggest a potential
sigma-1 receptor-mediated involvement of fluvoxamine in
mechanisms of neuroplasticity (Hashimoto, 2009).
Although less well defined, the range of observed
clinical effects is also consistent with sigma-1 receptor
agonism and there are preliminary suggestions that
fluvoxamine may also help to improve learning
mechanisms.
Fluvoxamine significantly improved performance in
the digit symbol substitution test (p¼0.02 vs. baseline)
in a double-blind, randomised study (Perez and
Ashford, 1990). In another study in 51 patients
hospitalised for a major depressive episode, 4 weeks
treatment with fluvoxamine resulted in significant
symptomatic remission with higher total Wechsler IQ
scores and a lower incidence of cognitive impairment
in treatment responders (Mandelli et al., 2006). More
recently, fluvoxamine improved cognitive impairments
in a patient with schizophrenia an observation
putatively linked to sigma-1 receptor agonism (Iyo
et al., 2008).At present, it is difficult to assess the
relevance of evidence that a sigma-1 receptor agonist
fluvoxamine has beneficial effects on cognition in
particular patient groups, such as the elderly. There are
no reports showing that fluvoxamine has clinical
superiority over other SSRIs in elderly patients with
significant cognitive dysfunction although case reports
may exist. Nonetheless, it is shown that sertraline is a
sigma-1 receptor antagonist, and that paroxetine does
not bind to sigma-1 receptors. In order to assess the role
of sigma-1 receptor agonism in the mechanism of
action, further detailed, randomised, double-blind
controlled studies of SSRIs (fluvoxamine vs. sertraline
or fluvoxamine vs. paroxetine) will be necessary.It is
suggested that sigma-1 receptor agonists can serve as a
regulator of ATP production and bioenergetics with the
cell, suggesting that sigma-1 receptor agonists might
have beneficial effects on the cell (Hayashi and Su,
2007; Hayashi and Stahl, 2009). Therefore, in terms of
patients with dementia with or without depression, we,
therefore, believe that a SSRI (e.g. fluvoxamine) with
sigma-1 receptor agonist activity might have beneficial
effects on cognition as compared with an SSRI with no
sigma-1 receptor agonism.
Figure 2. Effects of three SSRIs (fluvoxamine, sertraline, paroxetine) on NGF-induced neurite outgrowth in PC12 cells. Fluvoxamine (data show the
meanSEM [n¼6]), paroxetine (meanSEM [n¼6]), sertraline (meanSEM [n¼6]). p<0.05, p<0.001 compared with control (NGF alone group).
þþþp<0.001 compared with fluvoxamine (10.0mM) plus NE-100 group. The figure is a slight modification from the article (Nishimura et al., 2008)
Copyright # 2010 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2010; 25: 193–200.
DOI: 10.1002/hup
cognition and depression 197
CONCLUSIONS
Patients with MDD experience a variety of symptoms
consistent with cognitive impairment, and it is
important for any selected antidepressant therapy to
cause no further cognitive impairment. A normally
functioning cognitive system is an important defence
mechanism against stress and can be fundamental to
minimising residual symptoms that impair remission
and recovery.
The secondary binding properties of antidepressants
may contribute differential positive and negative
effects on cognitive function. Accumulated preclinical
and clinical data support an antidepressant-like action
of selective sigma-1 receptor agonists. It is thought
that, overall, the activation of sigma-1 receptors may
contribute to the proper functioning of active ion
channels and signal transductions essential for physiological
functions of neurons (e.g. neurotransmitter
release). The activation of sigma-1 receptors may also
induce potentiation of neurotrophic factor signalling,
cellular differentiation and cell survival. Sigma-1
receptor ligands can modulate neurotransmitter release
through interactions with muscarinic, dopaminergic,
noradrenergic, serotonergic and histaminergic receptors
along with intracellular kinase and phospholipase
pathways. Chronic sigma-1 receptor activation also
contributes to the formation and recomposition of
membrane lipid rafts, with direct consequences for
neuroplasticity (Hayashi and Su, 2008).
Certain ligands of the sigma-1 receptor are neuroprotective
and appear to exert a potent neuromodulatory
role in the brain that may have relevance in the response
to anxiety and stress, depression, learning, cognition and
antipsychotic activity. Fluvoxamine is a potent sigma-1
receptor agonist that may have particular benefits in the
treatment of patients with severe MDD, those with
psychotic depression, those with comorbid anxiety and
those where any cognitive impairment could well
compromise the performance of their everyday tasks or
where a risk of cognitive failure would increase noncompliance
or raise the risk of accident.
The clinical potential of sigma-1 receptor agonists
(including fluvoxamine) is only just beginning to be
explored. The primary clinical targets of sigma-1 receptor
agonists in ongoing research include stroke, neurodegenerative
disorders, depression, bipolar disorder and
schizoaffective disorders (Hayashi and Su, 2008; Iyo
et al., 2008; Stahl, 2008).
ACKNOWLEDGEMENTS
The authors acknowledge the assistance of Solvay Pharmaceuticals
in providing logistical support for the preparation
of this manuscript. All the ideas, calculations, findings and
conclusions are those of the individual authors. The authors
have no conflict of interest.
caused many spikes of hypertension,which I found out later on I am very prone to from exercise or stress/adrenaline because I have aortic valve disease.They gave me clonodine but didn't instruct me to taper off slo-w-w-ly in order to avoid rebound hypertension 
The starting dose of lexapro was too high IMO and could have easily lead to vasospasm with the ongoing rapid vasoconstriction/norepinephrine surge which is common and unfortunately very dangerous with rapid detox, even in Hospital settings, which is where i was in Florida.
Hmmm. I'm toying with the notion to switch at a latter point to Luvox OR not, decisions, decisions! 
