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Keywords:

  • adverse effects;
  • central nervous system;
  • natural glucocorticoids;
  • neuropsychic effects;
  • synthetic glucocorticoids

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

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 5–10% 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

Table 1.  Glucocorticoid activity
Effects on glucose metabolismEffects on central nervous system
Effects on lipid metabolismEffects on bone and cartilage
Effects on protein metabolismEffects on muscular function
Effects on hydro-electrolytic balanceEffects on gastric secretion
Anti-inflammatory and immunosuppressive actionEffects on cardiovascular system
Effects on hemolymphopoietic tissueEffects on reproductive physiology

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 hormone–receptor complex either stimulates or suppresses the transcription of target genes, depending on cell type. Mounting evidence suggests, however, that NGC may also exert rapid non-genomic 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).

Table 2.  Relative potency and duration of action of cortisol and synthetic glucocorticoids
Duration of action (plasma half-life)GlucocorticoidEquivalent doses (mg)
Short (t1/2 8–12 h)Cortisol20
Intermediate (t1/2 12–36 h)Deflazacort6
Prednisone5
Prednisolone5
Methylprednisolone4
Triamcinolone4
Long (t1/2 36–72 h)Desamethasone0.75
Betamethasone0.60

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 2.5–3% 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

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

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

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

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.8–10 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 (light–dark 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 Cushing's syndrome (CS) and Cushing's disease (CD), psychiatric disturbances were reported in a high percentage of cases (57–83%).16–19 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 stress-induced hormone rises and memory disturbances in trauma-related psychiatric disorders.24

Intravenous administration of hydrocortisone 0.5 mg/kg transiently impaired hippocampus-mediated 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.28

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 Wegener's 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 4–8%.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.5,34,37–43‘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 5–10%.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 10–60% for psychiatric reactions (generally poorly defined) to SGC may be extrapolated from pediatric studies,48–50 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 SGC-related 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.37,38,40,55–57 Blood–brain 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,38,40,45,53–55 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, long-term 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 (4–10 days),53,65 or chronically,61 the subjects showed impairment of both hippocampus-mediated declarative memory and frontal lobe-mediated 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,69–72 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 3–11 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.38,76

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 low-affinity 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 first-line treatment.42

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

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 γ-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 fluorodeoxyglucose-positron 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, SGC-treated 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.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES