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.
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
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 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