Natural glucocorticoids (NGC) physiologically

modulate body homeostasis and coordinate adaptive

responses to stress, involving almost all organs and
tissues, including brain. Since their therapeutic availability,
synthetic GC (SGC) have been successfully
prescribed for a variety of diseases. Mounting evidence,
however, demonstrated pleiotropic adverse
effects (AE), including central nervous system (CNS)
disturbances, which are often misdiagnosed or
underestimated. The aim of the present study was
therefore to review and discuss the CNS effects of
both NGC and SGC. A detailed search was carried out
of the available literature using the PubMed (US
National Library of Medicine) database. Cortisolemia
plays a crucial role in control of behavior, cognition,
mood, and early life programming of stress reactivity.
Hypercortisolemia or SGC treatments may induce
behavioral, psychic and cognitive disturbances,
due to functional and, over time, structural alterations
in specific brain target areas. These AE are
generally dose and time dependent (infrequent
at prednisone-equivalent doses 20 mg/day) and
usually reversible. Pediatric patients are particularly
susceptible. Behavioral changes, including feeding
and sleeping modifications, are common. Psychic AE
are unpredictable and heterogeneous, usually mild/
moderate, severe in 510% of cases. Manic symptoms
have been mostly associated with short SGC
courses, and depressive disorder with long-term treatments.
Suicidality has been reported. Cognitive AE
peculiarly affect declarative memory performance.
Physiologic levels of NGC are essential for efficient
brain functions. Otherwise, hypercortisolemia and
SGC treatments may cause dose-/time-dependent
neuropsychic AE and, over time, structural alterations
in brain target areas. Clinicians should carefully
monitor patients, especially children and/or when
administering high doses SGC.

GLUCOCORTICOIDS (GC) ARE 21-carbon
steroid endogenous hormones secreted by the
adrenal cortex, and thus defined as corticosteroids
along with mineralcorticoids (MC) and androgens.1
In humans, cortisol (in rats, corticosterone) is the
major biologically active natural GC (NGC), the
production of which is tightly regulated by the
adrenocorticotropic hormone (ACTH), secreted
from the anterior pituitary gland in response to the
corticotropin-releasing hormone, in turn produced
by the hypothalamus.
NGC play a crucial role in the intermediate
metabolism and immune regulation, and orchestrate
body adaptive responses to stress (defined as a state
of threatened homeostasis), integrating permissive,
preparative, suppressive, and stimulatory effects
(Table 1).1,2
The GC activity, which involves the vast majority
of organs and tissues, including brain, is primarily
mediated by two types of cytoplasmic receptors,
namely MC receptor (MR) and GC receptor (GR),
having a different distribution and functional
pattern.1
MR show a high affinity for both GC and MC,
while GR have a 10-fold lower affinity for GC; GR are
widely represented in the central nervous system
(CNS), whereas MR are much more restricted, but
both are particularly abundant in the hippocampus.1
The hormonereceptor complex either stimulates
or suppresses the transcription of target genes,
depending on cell type. Mounting evidence suggests,
however, that NGC may also exert rapid nongenomic
effects, possibly via membrane or other
non-classical receptors.1
Synthetic GC (SGC) substantially share the same
mechanisms of action of the endogenous hormones,
displaying different levels of efficacy, potency and
activity duration, related to their pharmacokinetics
(Table 2).
SGC are essential for the treatment of various diseases
and, thus, widely prescribed. The prevalence of
their assumption is estimated to be approximately
1% in the adult general population, and 2.53% in
older adults.3,4
Most patients usually receive short courses of SGC
at low dose,3 which is conventionally defined as a
prednisone-equivalent dosage 7.5 mg/day.4
Since their therapeutic availability, mounting
evidence has demonstrated, besides the significant
benefits, also the SGC-related pleiotropic adverse
effects (AE), including CNS disturbances, which are
frequently underestimated or misdiagnosed.4,5 For
example, early in the course of treatment it is difficult
to differentiate mild reactions from the stress
responses elicited by the underlying disease for which
the SGC were prescribed. The aim of this paper was
therefore to review and discuss the available literature
on the CNS effects of both NGC and SGC.
METHODS
A detailed search in the PubMed (US National
Library of Medicine) database was performed using
the following key words: adverse effects, central
nervous system, cortisol, natural glucocorticoids,
neuropsychic effects, synthetic glucocorticoids. The
systematic review of the literature on the CNS adverse
effects of SGC was accomplished by selection of
articles published since their therapeutic availability
(1950). We analyzed a vast number of papers, mainly
consisting of single case or small case series reports.
An adequate meta-analysis could not be done on that
literature, and we reviewed the most quantitatively
and qualitatively relevant contributions.
RESULTS
Effects of natural glucocorticoids on central
nervous system
In various species, NGC optimal levels are required
for neuronal growth, differentiation, and survival,
and they positively modulate synaptic plasticity.6 In
humans, cortisol influences behavior, mood and cognitive
performance.1 The effects primarily depend on
different GR/MR ontogenic pattern and brain distribution,
and vary with gender, age, hormone concentrations,
timing and duration of exposure.1,7
Behavioral effects
NGC physiologically modulate early life programming
of stress reactivity, a phenomenon called developmental programming.7,8 Indeed, both animal and
human studies showed that prenatal exposure to GC
excess, due to maternal endogenous overproduction
or exogenous administration, may cause permanent
behavioral changes in offspring and induce neuroendocrine
and cardiometabolic lifelong disorders.810
These effects are transmitted across generations, suggesting
an epigenetic mechanism primarily involving
tissue-specific alternate first exons/promoters of the
GR gene.10
NGC control appetite, food-seeking and feeding
behavior,1 primarily acting in a feed-forward fashion
on the brain to activate pathways that implement
want appropriate to physiological needs.11 Appetite
normally peaks at the time of the natural hormone
circadian zenith. Depending on the available conditions,
increase in natural hormone levels stimulates
feeding, peculiarly promoting the intake of food rich
in fat and sucrose, and ultimately leading to weight
gain.11
Moreover, cortisolemia influences chronobiologic
awakening/sleeping rhythm, and its rise may induce
arousal and sleeplessness.1 The evening cortisol
increase that characterizes aging correlates with
impaired sleep, earlier time of arising, and higher
electroencephalographic beta activity during sleep.12
The cortisol/sleep correlations appear stronger in
male than in female healthy seniors.12
Animal and human studies indicate that the
behavioral NGC effects are dose dependent. In
mice, corticosterone low-dose administration, either
immediately before, during or after repeated forced
swim procedure, produces a rapid stimulation of
mobility, likely due to suppression of neural activity
in central stress circuits and consequent disinhibition
of regions involved in active behavioral coping.13
Otherwise, moderate/elevated corticosterone doses
for a prolonged period induce the appearance of
anxiety (lightdark box)- and depression (forced
swim test)-like behaviors, as well as changes in hippocampal
cell proliferation (as measured on immunohistochemistry)
and hippocampal volume, which
are prevented by co-administration of imipramine
and fluoxetine.14
Mood effects
The effects of cortisol on mood and affect appear to
be dose dependent. A transient moderate elevation in
cortisolemia due to acute stress has a protective effect
on mood in critical situations.15 Otherwise, in permanently
hypercortisolemic patients suffering from
Cushings syndrome (CS) and Cushings disease
(CD), psychiatric disturbances were reported in a
high percentage of cases (5783%).1619 Depressive
disorder is the most frequent diagnosis, while anxiety
disorder, mania or psychosis are less common.16,17,20
In these patients, cortisol level normalization
induces significant improvements in score for depression
and anxiety.20
Cognitive effects
Compelling evidence indicates that physiologic NGC
levels play an essential role in cognitive functions,21
due to influences on brain regions crucial to learning
and memory, such as prefrontal cortex, hippocampus,
and basolateral amygdala.22
NGC basal levels enhance memory consolidation
and retrieval, increasing hippocampal excitability
and synaptic plasticity, likely by shortening and narrowing
the neuron hyperpolarized refractory period
after an action potential,6 whereas the acute administration
in rats of corticosterone high doses negatively
affects these processes in a dose-dependent
way.23 Similarly, in humans, acutely heightened
cortisol levels reversibly impair long-term memory
functions, and inhibit traumatic memory retrieval,
suggesting a potential association between stressinduced
hormone rises and memory disturbances in
trauma-related psychiatric disorders.24
Intravenous administration of hydrocortisone
0.5 mg/kg transiently impaired hippocampusmediated
declarative memory (memory typically
tested by recall of word/fact lists) in both young and
elderly subjects, but decreased frontal lobe-mediated
working memory only in young participants.25
Reversible declarative memory deficits have been
reported in healthy adult volunteers receiving a single
high dose (160 mg/day), but not a low dose (40 mg/
day) of hydrocortisone.26
The increase in basal cortisol levels that characterizes
aging usually correlates with a decline of declarative
memory consolidation.1
Chronically hypercortisolemic CS and CD patients
show impairment of specific domains of cognition,
such as verbal learning, delayed recall and other
verbal functions, that are more affected than
non-verbal ones.27,28 Of note, a higher degree of
cortisol elevation is associated with a poorer
performance, suggesting biological specificity.27 The
deficits were found to improve with cortisol level
normalization.
As in animal models, prolonged hypercortisolemia
was associated with reduced hippocampal volume,
measured on magnetic resonance imaging (MRI),
which was partially reversed by cortisol decrease
following treatment.29
Effects of synthetic glucocorticoids on central
nervous system
Neurophysiologic studies demonstrated that the SGC
administration may induce dose-dependent changes
in adult brain electrical activity and neurochemistry,
30,31 and SGC treatments are frequently associated
with a variety of clinical sequelae on behavior, mood
and cognition, the real incidence of which is not
presently inferable from the literature, because few
controlled and validated studies have been so far
performed.
Behavioral effects
In a large population-based study, food-seeking
changes and increase in appetite with consequent
weight gain were found to be the most common SGC
behavioral AE, reported by 70% of the long-term
users.32
In a cohort of Wegeners granulomatosis patients
treated with prednisone, more than one-fifth of subjects
gained and maintained _10 kg in the first year
of SGC treatment.33 Weight gain did not correlate
with the cumulative SGC dose.33
In different trials, the range of the mean bodyweight
increase over 2 years was estimated to be
48%.34
Sleep disturbances were found to be the next most
common AE in long-term SGC treatments.32 Interestingly,
while weight gain was significantly associated
with longer duration of administration, sleep disturbances
were strongly related to the increase in daily
dose.32 Split-dose therapy tends to be particularly
troublesome, owing to the evening dose promoting
sleeplessness.4
Complaints of insomnia, fussiness, hyperactivity,
and irritability were observed in 73% of infants on
systemic prednisolone treatment with a minimum
starting dose of 0.5 mg/kg per day for hemangiomas.35
In pediatric patients, prednisone high dosages
during nephrotic syndrome relapses were found to
cause irritability and tendency to aggression, the
severity of which required parental assistance for the
significant difficulties in caring. Children 10 years of
age were particularly affected.36
Psychic effects
The SGC-related psychic effects have been found to
occur in quantitatively/qualitatively distinct forms,
ranging from an initial slight increase in the overall
sense of well-being (independent of improvement in
their underlying disease activity)4 or low-grade mood
changes, such as euphoria, grandiosity, emotional
lability, depressed or elated mood, up to severe psychiatric
disorders and suicidality.5,34,3743 Severe psychiatric
AE (PAE) has been defined as a constellation
of major symptoms consistent with a diagnosable
affective syndrome, psychotic disorder, delirium
or another psychiatric condition.42 Few studies,
however, used clearly defined diagnostic criteria to
characterize the SGC-related PAE, or performed validated
epidemiological assessments. Moreover, in the
literature the term steroid psychosis has been frequently
and even inappropriately used to describe
a variety of distinct conditions, not all of them
psychotic.
Studies reporting the PAE frequency have cited
rates from 1.3% to 62% of adult treated
patients.38,42,44,45 This wide range reflects both the
unpredictability of these reactions and the variability
in definitions.
PAE were found to be mild or moderate in approximately
one-third of cases, while severe symptoms
were observed in 510%.37,38,40,46 Moreover, in adult
patients with SGC-related psychosis, suicidal ideation,
suicide attempts, and completed suicide have
been reported.38,42,43,47
Rates of 1060% for psychiatric reactions (generally
poorly defined) to SGC may be extrapolated
from pediatric studies,4850 psychotic symptoms being
quite frequent.50
Adults studies suggest a presumable threshold dose
of _20 mg/day of prednisone (or equivalent) for PAE
development,42,51 and patients receiving more than
40 mg/day appeared to be at the greatest risk.44 SGCrelated
psychoses, however, may occur at very low
dosages.52,53
PAE mostly develop within the first weeks of
administration, but the onset may occur within few
days of SGC treatment47,53,54 or at any point during
treatment, including withdrawal (in general after
long courses at high doses).38,42
PAE usually display rapid resolution after SGC
reduction or discontinuation, and frequently restart
on dose increase/re-administration.5,37,38,50,55 Sometimes,
switching to alternative SGC was found to be
helpful.50
Controversy exists whether female gender constitutes
a predisposing factor,37,38,55 and whether the
patient psychiatric history or previous lifetime GC
exposure plays a role.37,38,40,5557 Bloodbrain barrier
damage and hypoalbuminemia have been proposed
as possible risk factors.58,59 Some evidence suggests
that dexamethasone is associated with more severe
PAE than prednisone or prednisolone, likely due to
pharmacokinetic differences.50,60 Moreover, it is
debated whether the alternate-day schedule of SGC
administration might reduce the PAE incidence and
severity.5
Notably, the duration of treatment may influence
the PAE qualitative aspects. Brief SGC bursts at
moderate/high dose have been mostly associated
with symptoms of mania and, less frequently, with
depression,38,40,45,5355 usually reversible with treatment
discontinuation or reduction.55 Pulse i.v.
therapy with methylprednisolone high doses was
mainly associated with the rapid onset of manic or
hypomanic symptoms.40 Depressive episodes and
suicide attempt by self-mutilation have been infrequently
reported.40
Otherwise, unlike short-term treatments, longterm
therapies appeared to be more associated with
depressive disorder,42,45 which usually stabilize over
time.61
Recurrence of SGC-induced mood disorders was
reported to have interesting clinical features, such as
subacute onset, manic predominance, and high frequency
of accompanying psychotic symptoms than
in single-episode cases.62 In this regard, the potential
risk of multiple courses of SGC treatment should be
further explored.
Anecdotal reports underline that not only systemic
administration, but also intra-articular injection of
SGC may be associated with acute onset of transient
psychotic symptoms, such as severe agitation, paranoid
delusion, visual and auditory hallucinations.63,64
Cognitive effects
Cognitive impairment is a common, dose-dependent
AE of SGC.65,66 When moderate/high doses were
administered acutely,25,53 in two repeated short
courses (3 days) with washout interval,57 over a
longer period (410 days),53,65 or chronically,61 the
subjects showed impairment of both hippocampus
hippocampusmediated
declarative memory and frontal lobemediated
working memory.
Memory impairment was reported in 71% of
treated patients, and marked distractability was identified
in 79% of cases,47 and cognitive performance
reassessment (a mean of 4 years after the original
evaluation) provided evidence that the initial deficits
remained relatively stable over time.61
Prolonged exposure to SGC moderate/high doses
may produce cumulative and potentially long-lasting
influences on specific brain area morphology, such
as smaller hippocampal67 and amygdala68 volumes.
Right amygdala volume reduction significantly correlated
with duration of treatment.68
In pediatric, adult, and elderly patients treated
with SGC high dose,6972 severe cognitive impairment,
including deficits in attention, concentration,
memory retention, mental speed and efficiency, was
also described. In adulthood, alterations were found
to be largely reversible 311 months after SGC discontinuation,
70 while children were particularly susceptible,
showing only partial recovery,69 as well as a
long-lasting reduced hippocampal volume on MRI
and decreased activity on single-photon emission
computed tomography in left frontal and parietal
lobes.73
Otherwise, SGC low doses did not affect adult
cognitive functions in both short74 and long-term
courses,75 and prednisone chronic administration
did not induce negative effects on hippocampal
volume.75
Management of glucocorticoid-related
neuropsychiatric adverse effects
The available literature on preventing or reversing the
cognitive and psychiatric SGC-related AE is mainly
based on anecdotal reports, and definitive strategies
have so far not been standardized.
A preventive approach may be achieved by using
SGC doses as low as possible, particularly in pediatric
patients, and by tapering long-term therapy as gradually
as possible, especially in high-dose courses.
In treating neuropsychiatric AE, the first intervention
is the SGC discontinuation/reduction, which
usually produces symptom remission in 2 weeks
several months; the use of addressed pharmacotherapy
dramatically reduces this period.40,42
Electroconvulsive therapy was proved useful in adult
and pediatric patients with severe psychoses refractive
to medical treatment
A standardized pharmacological strategy to face
SGC-related neuropsychiatric AE is not presently
defined. Lamotrigine, an inhibitor of glutamate
release through blockade of voltage-sensitivity
sodium channels and stabilization of the neuronal
membrane, led to significant improvement of declarative
memory impairment,77 and was successfully used
in prophylaxis against SGC-induced mania.78 Phenytoine,
an inhibitor of both glutamate release and
glutamate actions by blocking sodium channels, was
found to prevent SGC-induced hypomania, but not
the declarative memory impairment.79
In turn, administration of memantine, a lowaffinity
antagonist to N-methyl-D-aspartate-type
receptors, provided improvements in declarative
memory, but not in mood.80
Levetiracetam did not significantly improve mood
and cognition in prednisone-treated patients.81
Positive results in PAE treatment were obtained
with mood stabilizers, including carbamazepine, valproic
acid40 and lithium,82,83 which proved to be also
prophylactic.40 Tricyclic antidepressants have been
used with contrasting results,38,40,84 whereas selective
serotonin re-uptake inhibitors,85,86 and venlafaxine87
were successful.
Both typical,40,88 and atypical antipsychotics, such
as olanzapine89,90 or risperidone,91 even in combined
therapy with valproic acid,92 provided positive results
in adult patients, while phenothiazines, such as
promethazine93 or chlorpromazine,94 and risperidone,
95,96 obtained benefits in pediatric patients.
Atypical antipsychotics were found to induce fewer
dystonic reactions or other extrapyramidal AE than
typical ones, so they have been recommended as firstline
treatment.42
CONCLUSIONS
The extensive literature review highlights both the
physiological and iatrogenic GC effects on CNS. In
humans, basal NGC activity entails positive influences
on behavior, cognition and mood, which seem
to be primarily accomplished by favorable effects on
synaptic plasticity and a neuroprotective action,
likely mediated by the activation of tyrosine kinase
neurotrophin receptors.97 In turn, the exposure to
both NGC and SGC excess exerts dose-dependent
negative effects on neuronal viability, and induces
behavioral changes, cognitive dysfunctions and psychopathologic
reactions, ranging from low-grade
mood disturbances to severe affective disorders and
psychosis, as well as, over time, structural alterations
in specific brain area.
Notwithstanding the wide therapeutic use of SGC,
the exact incidence of their neuropsychiatric AE
cannot be presently drawn from the literature, given
that they are not ever reported or systematically
assessed. Evidence has emerged, however, that SGC
neuropsychiatric sequelae are common, usually dose
/time related and reversible, mostly mild to moderate
but potentially severe, and often requiring psychiatric
treatments that are not presently standardized.
Indeed, little attention has been hitherto directed to
therapeutic strategies and long-term outcome
assessment.
The pathophysiology of GC-related AE on CNS
remains unclear. The rapid and reversible decline in
declarative memory observed after high-dose administration
is not primarily attributable to neuronal
death, but likely reflects functional alterations,98 due
to changes in g-amino butyric acid signalling,
increased glutamate concentration in synapses,
concomitant elevation of cytosolic calcium, and
GC-induced reduction of hippocampal glucose
uptake,99 as demonstrated on fluorodeoxyglucosepositron
emission tomography (PET).100 Moreover,
GC have been reported to directly modulate the neuronal
activity of specific cholinergic and dopaminergic
systems in the brain.101
The structural brain changes observed in chronically
hypercortisolemic or long-term SGC-treated
patients may be related to dendritic atrophy and
reversible suppression of neurogenesis.102,103
Of note, a large decrease in regional cerebral blood
flow of cerebellum, left visual cortex, and right posterior
medial temporal lobe, reaching the maximum
in the parahippocampal gyrus, was demonstrated on
H(2)(15)O-PET in healthy male subjects given SGC,
and correlated with declarative memory impairment
on episodic tasks.104
Further studies will allow better identification of
the underlying mechanisms and possibly prevent
SGC-related neuropsychic AE, the real incidence of
which must be assessed in rigorous, validated studies.
Ultimately, clinicians should be aware, and
patients, family or caregivers should be advised on
the potential CNS consequences of SGC treatment.
Careful attention should be provided in treating
pediatric patients. Because data suggest the rapid
onset of these AE, clinical follow up is important
soon after initiating therapy, especially for high-dose
treatment.
Thus, along with monitoring blood pressure, glycemia,
lipidogram, and bone density over time, SGCtreated
patients should be asked about appetite,
weight, insomnia, memory, mood swing, and psychiatric
symptoms. All patients developing PAE while
taking SGC should be evaluated for suicidal ideation.
Close cooperation and support by psychiatrists will
contribute to improve quality of life in patients
undergoing SGC treatment.