by David R. Spiegel, MD; Lindsay Holtz, MD; and Kokil Chopra, MBBS
Drs. Spiegel, Holtz, and Chopra are from Eastern Virginia Medical School, Norfolk, Virginia.

Psychiatry (Edgemont) 2010;7(4):31–36

Funding: There was no funding for the development and writing of this article.

Financial disclosure: The authors have no conflicts of interest relevant to the content of this article.

Key words: mania, systemic lupus erythematosus, immunosuppresants, inflammation


Systemic lupus erythematosus is a chronic inflammatory condition caused by an autoimmune disease. Systemic lupus erythematosus has been described as inducing neuropsychiatric symptoms, including mania and psychosis, in approximately 14 to 80 percent of systemic lupus erythematosus patients. We present and discuss the differential diagnoses in a patient with mania and systemic lupus erythematosus being treated with immunosuppresants and also with a history of glucose-6-phosphate dehydrogenase deficiency. Finally, we review the potential pathogenesis of mania due to an inflammatory-mediated etiology and how this may be used to partly explain the pathogenesis of primary mood disorders.


Systemic lupus erythematosus (SLE) is a chronic inflammatory condition caused by an autoimmune disease. SLE has been described as inducing neuropsychiatric (NS) symptoms, including mania and psychosis,[1] in approximately 14 to 80 percent of SLE patients.[2] Unfortunately, no one set of criteria has been accepted as diagnostic for NS manifestations of SLE. We present a case of mania with psychosis in a patient with SLE and discuss the differential diagnosis of NS-SLE including steroid-induced mood and psychotic disorder (SIMPD), mood disorder with psychotic features, and glucose-6-phosphate dehydrogenase (G6PD) deficiency psychosis. Additionally, we discuss an inflammatory-mediated hypothesis for the pathogenesis of mania due to SLE and its potential relevance in the neurobiology of primary mood disorders.

Case Report

Our patient was a 21-year-old black man, diagnosed with SLE in 2004. He was admitted to our hospital with a chief complaint of altered mental status. Psychiatry was consulted because he was exhibiting “mania and psychoses (M/P).”

Three to 4 weeks prior to admission, our patient experienced decreased need for sleep, elevated mood, and delusions status post grand mal seizure. An outside community hospital diagnosed the patient with a seizure secondary to SLE and prescribed him prednisone 20mg daily, which the patient took as prescribed; however, his manic-type symptoms increased and he was transferred to our facility.

Past medical history was significant for diagnosis of SLE in 2004 and G6PD deficiency. There was neither family nor personal history of psychiatric illness.

Our patient denied alcohol or illicit substance usage and blood alcohol level and urine drug screen were unremarkable.

Remarkable laboratory results included elevated anti-DNA, anti-Smith, anti-ribonucleoprotein antibodies, and haptoglobin; while perinuclear antineutrophil cytoplasmic antibody (P-ANCA) screen was positive. Both C3 and C4 complement factors were decreased. Vitamin B12 and folic acid were both within normal ranges. Blood/cerebrospinal fluid (CSF) cultures were negative for immune pathogens and chest roentgenogram was unremarkable.

Computed tomography (CT) scan of the head without contrast revealed “diffuse atrophy” that appeared to be advanced for the patient’s age. Despite his history of G6PD deficiency, hemolytic anemia was deemed unlikely because bilirubin values were within normal limits. Ribosomal P protein Antibody (Ab), oligonucleotide bands, and immunoglobulin (Ig) G Ab were positive in the CSF although cardiolipin Ab was negative.

During our interview, the patient reported a one-month history of euphoria, denying the need for more than one hour of sleep per night, with pressured speech and flight of ideas. The patient had multiple grandiose delusions, such as being a detective for the police and owning a car dealership. He denied any history of major depression, suicidal or homicidal ideations, auditory hallucinations (AH), and visual hallucinations (VH). Cognitively, he was oriented x3 and intact. His delirium screen, measured by the Confusion Assessment Method in the ICU,[3] was negative (Table 1). He scored 35/60 on the Young Mania Rating Scale (YMRS).[4] The patient was started on prednisone 60mg/day, valproic acid (VPA) 1250mg intravenous (IV) daily (20mg/kg), olanzapine (OLZ) 10mg intramuscular (IM) twice daily (BID), and lorazepam (LOR) 1mg IM BID.

Three days after the initial interview, the patient’s dose of prednisone was decreased to 40mg daily due to concern of SIMPD, (including AH and paranoid delusions; scoring 58/60 on the YMRS). OLZ was increased to 20mg IM BID while VPA was increased to 1750mg IV daily with a level of 98µg/mL. The patient continued without delirium. Eight days after our initial evaluation, treatment with IV cyclophosphamide 750mg/mÇ was initiated.

One week after cyclophosphamide administration, the patient became more cooperative and his YMRS decreased to 34/60. Symptoms of M/P continued to fluctuate over the next month. During this period, lorazepam was increased to 2mg IM BID, OLZ to 20mg IM BID, and VPA to 1gm IV BID. After a month of prednisone 40mg/day, his dose was tapered. His YMRS decreased to 30/60. Approximately eight weeks after admission, our patient’s M/P improved dramatically, which coincided with a reduction in prednisone to 20mg/day and seven days after his second dose of IV cyclophosphamide. Before the second dose of the latter, his YMRS was 26/60. At nine weeks, our patient was euthymic and without psychoses (YMRS=0) and psychotropics were discontinued. He was discharged on prednisone 15mg/day and as of three months of follow up, he remained adherent with prednisone and was euthymic.


NP symptoms are not uncommon in SLE.[2] Our patient presented with a mood disorder characterized by M/P. According to the American College of Rheumatology, this sequella, when associated with SLE, is neuropsychiatric lupus (NP-SLE).[5] No one finding is diagnostic for NS-SLE; however, increasing research has found it to be associated with certain autoantibodies.

Autoantibodies detected in the serum and/or CSF that have been reported to segregate with patients presenting with NP-SLE include the following: 1) antineuronal antibodies (including anti-DNA antibodies cross-reactive with N-methyl-D-aspartate (NMDA) receptor, 2) antiribosomal P antibodies, 3) antiphospholipid antibodies, and 4) antiendothelial cell antibodies.[6]

Antiribosomal P antibodies (with its low positive predictive value)[7] and possibly anti-NMDA (NR2) receptor antibodies have been posited to cause diffuse NS events (e.g., psychosis, depression, cognitive impairment) through a direct effect on neuronal cells; a critical factor in this is the ability of these antibodies to directly access neuronal cells either through intrathecal production or via passage from the circulation across a permeabilized blood-brain barrier.[8] The latter could develop via antiendothelial cell antibodies, activating the endothelium inducing the synthesis of proinflammatory cytokines and chemokines and expression of adhesion molecules, leading to increased permeability of the blood brain barrier.[9]

Furthermore, it has been reported that neurodegeneration of the midbrain’s ventral tegmental area (VTA), and its dopaminergic projections, occurs. Additionally, there is evidence of degeneration of other mesolimbic structures, including the hippocampus, amygdala, and hypothalamic areas.[10] There are five frontal-subcortical circuits providing the neuroanatomical basis for movement and behavior. Each of the circuits shares the same member structures including the frontal cortex, striatum, globus pallidus/substantia nigra, and thalamus. Neurotransmitters, like dopamine, mediate and modulate the neurotransmission through the circuits. Frontal-subcortical circuits are named according to their cortical site of origin. For example, the anterior cingulate circuit is involved in generating motivated behavior, and lesions in this circuit typically result in apathy. The orbitofrontal circuit mediates empathic and socially appropriate behavior. Personality change with disinhibition is evident in orbitofrontal circuit dysfunction. While speculative, degeneration of the VTA in the orbitofrontal circuit could result in a similar presentation as our patient.[11]

Moreover, it has been demonstrated that in the hippocampus of lupus-prone mice, the dendritic complexity of pyramidal neurons is strikingly reduced compared to control mice.[12] Furthermore, early treatment with cyclophosphamide (CY) can prevent the expected neuronal atrophy of dendritic spines in these same mice. Sakic et al[12] propose that CY, a cytotoxic alkylating and immunosuppressant agen, may reduce infiltration of cytotoxic lymphocytes into the brain and/or normalize activity in the hypothalamus-pituitary-adrenal axis. In regard to the immune hypothesis, there is evidence that mononuclear cells penetrate through the damaged blood brain barrier and infiltrate choroid plexus and brain parenchyma. Thus, without CY being able to enter the brain in any significant concentration, CY treatment may reduce the number and activity of circulating lymphocytes, which, upon entering the brain, may synthesize brain reactive antibodies (i.e., antiribosomal P), cytokines, and other metabolites potentially harmful to neuronal development, maturation, and survival.[13] While neuropathogenic mechanisms need replication in human studies, there have been reports of similar neuropathology developing in NP-SLE in humans (i.e., hippocampal degeneration, which compromises hippocampal function).[14]

This hippocampal pathology from NP-SLE mania may shed further evidence on the neuropathology of primary mood disorders as the hippocampal formation (dentate gyrus, Ammon’s horn, subiculum, and parahippocampal cortex) has been implicated in mood disorders as several, though by no means all, magnetic resonance imaging (MRI) studies have found smaller hippocampal volumes in major depression and bipolar disorder (BD). Also, preliminary studies suggest, as in the prefrontal cortex, the presence of synaptic and dendritic pathology in the hippocampal formation, especially in BD. These studies have found dendritic changes suggestive of decreased afferent synaptic innervation or activity, a possibility supported by a reduced expression of synaptic protein genes in BD, especially in the subiculum.[15]

If this immune hypothesis is accurate, this could explain why our patient responded robustly to CY, rather than the combination of OLZ, VPA, and LOR. However, while VPA’s mechanism of action was initially found to be primarily related to neurotransmission and modulation of intracellular pathways, it has been demonstrated that it is neuroprotective in several models of neurodegenerative diseases.16 Additionally, while the underlying mechanisms remain uncertain, evidence for a neuroprotective effect of atypical antipsychotics has been reported as they may counteract some progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience.[17]

In addition to autoantibodies, NS-SLE manifestations have been connected with findings of SLE activity, such as decreased C3 levels.[18] The usefulness of MRI in diagnosing NS-SLE is controversial. Up to 67 percent of patients with NS-SLE have abnormal MRI scans with decreased cerebral volume as compared to healthy individuals.[19] Acute psychotic symptoms caused by NS-SLE tend to occur early in its course; however, time of symptom development is not useful for the diagnosis.[20]

The complex differential diagnosis for this patient included SIMPD. With its elusive pathophysiology and its uncommon occurence,[21] some studies support corticosteroids increasing dopamine levels.[22] In a study of 92 SLE patients treated with corticosteroids, five percent developed steroid-induced psychosis.[21] Most patients with SIMPD present with mood symptoms and about 13 percent of patients present with psychotic symptoms.[23] The majority of patients (57%) develop symptoms approximately two weeks after starting corticosteroids.[24] Seventy-seven percent of cases consisted of patients on corticosteroid doses greater than 40mg every day with an average dose of 59.5mg/day.[21] In the Boston Collaborative Drug Surveillance Program, 463 patients treated with 40mg or less of prednisone daily were followed, and only 1.3 percent of these patients experienced acute psychiatric reactions associated with the steroids. The likelihood of developing steroid-induced psychiatric symptoms increased to 4.6 percent when the patient is treated with a higher dose of prednisone (41–80mg per day), which increased to 18.4 percent in those receiving greater than 80mg/day.[25] Treatment includes tapering of the corticosteroids, and the average time for symptom resolution is 21 days.[26]

Given our patient’s age, BD Type I (BPAD/TI) also needed to be considered in the differential. Our patient met the Diagnostic and Statistical Manual Fourth Edition Text Revision (DSM-IV) criteria for a manic episode.[27] More than 50 percent of BPAD/TI patients also have symptoms of psychosis.[28] Only longitudinal follow up can further delineate if our patient did have BPAD/TI; however, in combination with his history and laboratory results, the diagnosis of Mania due to SLE, appeared more likely. Nonetheless, one report notes that BPAD/TI has a six-percent comorbidity with SLE.[29]

Our patient did have G6PD deficiency, which can cause psychosis. G6PD psychosis has been reported to present with M/P and hyperbilirubinemia.[30] Our patient’s bilirubin levels were within normal limits, thus we felt that this diagnosis was lower in the differential.

Our patient’s M/P was treated with VPA and OLZ. However, as his CS dosage was increased, these symptoms started to accentuate despite supratherapeutic doses of OLZ[31] and a therapeutic level of VPA. It was not until the second trial of cyclophosphamide and decreasing the dosage of CS that significant improvement of the symptoms occurred. Our patient had a new onset seizure shortly after his psychiatric changes began, which could herald NS-SLE. As many as 33 percent of NS-SLE patients experience seizures.[32] The latter have been associated with anti-SM antibodies,[2] which occurred in our patient.

Differentiating between SIMPD and NS-SLE is challenging (Table 2 ).[23] A patient is more likely to develop neuropsychiatric changes caused directly by SLE rather than steroids.[2,23] In addition, given the low dose of steroids when his manic symptoms began, makes SIMPD less likely as the precipitant of his mood episode.

With this caveat, his manic symptoms seemed to be accentuated after treatment with prednisone 60mg/day. Furthermore, these symptoms improved dramatically after prednisone was decreased to 20mg/day, albeit the second dose of cyclophosphamide had been given one week earlier. Thus, our patient’s ultimate diagnosis could have plausibly been a manic episode due to NS-SLE and SIMPD. Even though there have been reports of successful treatment of mania due to SLE with antipsychotics,[1] our case seems to support that NS-SLE may respond more robustly to cyclophosphamide (and prednisone). Additionally, in one study, twenty-eight DSM-IV BD patients were experiencing a depressive or mixed episode and were on a stable dose of a mood stabilizer or atypical antipsychotic medication. These subjects were randomized to receive six weeks of double-blind placebo or celecoxib (400mg/day) treatment. Mood stabilizer or antipsychotic medication remained at the same doses during the trial. The authors reported that adjunctive treatment with celecoxib could have produced a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes.[33]

In conclusion, while we feel our case report does generate an interesting differential diagnosis, the similar phenotypic expression between our patient with probable secondary mania and primary mania, affords us the opportunity to add further evidence about inflammatory mediated mechanisms in the pathogenesis of primary mood disorders and the need for further research in immune hypotheses of mood disorders.

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