The Successful Treatment of Mania Due to Acquired Immunodeficiency Syndrome Using Ziprasidone: A Case Series

A n acute manic episode, whether of primary or secondary origin, is frequently a medical emergency that proves to be a significant health risk for those who suffer these episodes. HIV, the causative pathogen in AIDS, has been reported to induce manic symptoms, especially with a CD4 count less than 100 cells/mm ³ . 1 Mania due to AIDS displays the classic characteristics of secondary mania such as an identifiable medical cause, a later-than-average age at onset, and development in patients who lack a previous personal or family history of mania. 2 – 5 Mania may result from the ability of HIV to traverse the blood-brain barrier, causing an immune activation which produces toxic cytokines and metabolites that primarily affect the subcortical brain structures, such as the basal ganglia and periventricular white matter. 3 , 6 This reaction can ultimately lead to neuronal cell apoptosis. Nonetheless, it should be stated that while the prevalence of mania due to AIDS has been reported to be between 4% and 8%, both at our institution and more nationally, the prevalence of depression due to AIDS is still significantly higher, with reports between 4% and 22% for HIV seropositive men and between 2% and 18% for HIV seropositive women. 1

This case series investigates the efficacy in using the atypical antipsychotic ziprasidone to treat mania due to AIDS, which has previously been FDA approved for the management of bipolar mania. As far as we are aware, the reported use of atypical antipsychotics in the treatment of mania due to AIDS has been limited to risperidone and olanzapine, which have been shown to be efficacious. 7

Case 1

Our patient was a 47-year-old African American woman admitted to the internal medicine service due to altered mental status/agitation. Due to these symptoms, 1 day after her arrival, our service was consulted. Her past medical history was significant for AIDS (most recent CD4 count of 12 cells/mm ³ ) and suspected progressive multifocal leukoencephalopathy. Our patient had no prior history of any psychiatric illness.

Upon examination by our team, the patient was highly agitated and disruptive. Her speech was rapid, pressured, and tangential. A full mental status exam was unobtainable as our patient’s thought processes were remarkable for flight of ideas; however, of note, she did demonstrate grandiose and religious delusions. Symptoms of mania were assessed using the Young Mania Rating Scale (YMRS) with our patient scoring 44. We started the patient on ziprasidone, 10 mg i.m. t.i.d.

Two days after starting ziprasidone, her YMRS score decreased to 8. At this time, we changed the ziprasidone dosage to 80 mg p.o. b.i.d. with lunch and dinner. Unfortunately, after 2 days of oral ziprasidone, the patient’s YMRS score had risen to 18. She described her mood as “fine” with an expansive affect and her thought content was significant for grandiose delusions. Following this assessment, the dosing of the ziprasidone was changed back to 10 mg i.m. t.i.d.

The following day, our patient’s YMRS score had dropped to 9. She was alert and cooperative. The patient did have a slight pressure of speech. Our patient was discharged the following day with ziprasidone 80 mg p.o. t.i.d. with meals. On 4 and 6 weeks follow-up, the skilled nursing facility staff reported that the patient was in a similar condition as per discharge. This patient was not placed on antiretroviral therapy at the time of discharge.

Case 2

Our patient was a 36-year-old African American woman, with a 17-year history of HIV infection, presenting to the emergency room with a 4-week history of “odd behavior and confusion.” Physical examination was unremarkable. MRI of the brain and chest radiograph was normal. Laboratory tests included vitamin B ₁₂ , folic acid, ammonia, arterial blood gases, thyroid function tests, complete metabolic profile and urinalysis, and these were all within normal limits. CSF profile/culture/gram stain, rapid plasma reagin, blood/urine cultures, and cryptococcal antigen were negative. Urine drug screen and blood alcohol level were also negative.

On psychiatric evaluation, our patient was noted talking to herself and had religious and grandiose delusions. For instance, she believed that God had “cured” her of HIV. Although “cured,” she endorsed compliance with her antiretrovirals despite a CD4 cell count of 87 cells/mm ³ .

The patient had no insight into her condition and described her mood as “great.” She denied alcohol or illicit drug use. She denied any hallucinations, depression, or suicidal/homicidal ideations. Our patient had no prior psychiatric history, and she had not been taking psychotropics in the past. The patient scored a 27/30 on the Mini-Mental Status Examination (MMSE) and a 36 on the YMRS.

We treated the patient with ziprasidone, 10 mg i.m. t.i.d. After 3 days on this ziprasidone regimen, her YMRS score decreased to 11. On day 4 of the hospitalization, her ziprasidone dosage changed to 80 mg p.o. b.i.d. with lunch and dinner. She was discharged from the hospital on this ziprasidone regimen and on antiretroviral therapy. Unfortunately, this patient was lost to follow-up.

Case 3

Our patient was a 45-year-old African American woman with a past medical history significant for AIDS (most recent CD4 + lymphocyte count of 44 cells/mm ³ ) as well as long-standing alcohol and cocaine dependence. She was admitted to the hospital for treatment of Pneumocystis carinii pneumonia. This patient also had a remote history of syphilis which she reported having had treated in the past. Cerebrospinal fluid was remarkable for a positive venereal disease research laboratory test. The patient was treated with intravenous penicillin G for possible neurosyphilis.

An MRI of her head showed mild to moderate atrophy as well as periventricular white matter disease. After receiving treatment for 3 days with intravenous antibiotics, we were consulted for a capacity evaluation.

At the time of our initial consultation, her mood was “good” with episodes of inappropriate laughter. She was very talkative during the exam and displayed loud and rapid speech. Although not overtly hypersexual, she was affectionate and did insist on a hug from the examiner at the conclusion of the interview. The patient reported the delusion that her HIV had been cured several years ago and she had “no problems.” She denied auditory or visual hallucinations. Her insight and judgment were poor. Cognitively, our patient was oriented ×2. She scored 19/30 on the MMSE and 23 on the YMRS.

She was treated with ziprasidone, 40 mg p.o. b.i.d. with lunch and dinner, for her manic symptomotology, which we increased to 80 mg p.o. b.i.d. with lunch and dinner after 2 days. Her manic symptoms improved after 3 additional days on the higher ziprasidone dosage, with her YMRS score decreasing to 10. Our patient was appointed a medical guardian to assist in skilled nursing facility placement. On 1-month follow-up, her manic symptoms continued to be attenuated on ziprasidone, 80 mg p.o. b.i.d. with lunch and dinner. The patient’s primary care team elected not to place the patient on antiretroviral therapy.

DISCUSSION

Our three patients’ manic episodes fit the description of a secondary mania rather than primary mania. That is, presenting at a late age, having a medical condition that can account for the mania (AIDS), and no personal or family history of a manic episode. Specifically, advanced HIV disease (AIDS) is a common setting for mania due to AIDS. 5 Limitations of our case series include that the 3 cases presented represent a homogeneous group. Progressive multifocal leukoencephalopathy may have been present in up to two of the three patients and neurosyphilis, a known cause of mania, 8 may have been etiologic in one. Additionally, although head neuroimaging showed white matter hyperintensities, possibly consistent with progressive multifocal leukoencephalopathy in two of our patients, we were unable to locate any published reports associating mania with white matter disease or progressive multifocal leukoencephalopathy. 5 Nonetheless, while we most likely attribute the manic symptoms as a result of the neuropathology caused by HIV directly, as we discuss below, white matter disease could theoretically result in symptoms of disinhibition.

As discussed earlier, HIV preferentially affects subcortical brain structures, such as the basal ganglia. Furthermore, frontal-subcortical pathways have been described to control behavior. The circuitry includes the orbital frontal cortex (OFC), striatum (ST), globus pallidus (GP), and thalamus (TH). This circuit, which projects as OFC→ST→GP→TH→OFC, is considered to be an extension of the limbic system. A lesion involving this circuit, either in a specific region or its axonal connections between regions (i.e., white matter), may present with symptoms such as aggression, behavioral disinhibition and emotional lability. 9 A potential explanation for our patients’ manic symptoms may be explained by HIV’s predilection for basal ganglia and periventricular white matter and interrupting the frontal subcortical circuit.

The neural signaling in bipolar disorder remains elusive, although dopaminergic transmission seems to play a role, both by indirect evidence (i.e., efficacy of antipsychotics) and more direct data, such as increased dopamine (DA) 2 receptor density in psychotic patients with bipolar disorder. 10 Furthermore, one of the cell bodies of dopamine in the midbrain, ventral tegmental area, directly projects to the striatum indicating a possible role for dopaminergic transmission in the frontal-subcortical pathways, which we have proposed may be involved in the phenomenology of mania due to AIDS. 11

Ziprasidone is a 5-hydroxytryptamine (5-HT) 2/D2 antagonist. It has already been well documented that this antipsychotic is efficacious in the treatment of bipolar mania. 12 If indeed that DA-ergic transmission is involved in the pathophysiology of mania due to AIDS, then atypical antipsychotics, such as ziprasidone, offer a sound pharmacological treatment, based on receptor dynamics. Atypical antipsychotics are of particular importance in this patient population because of the subcortical involvement of the virus, making these patients at very high risk for extrapyramidal symptoms. Basal ganglia involvement as a sequelae of HIV infection is one postulated mechanism for such sensitivity. Subcortical involvement is seen with HIV associated cognitive/motor disorder, with extrapyramidal symptoms including psychomotor slowing and tremor. 13

Atypical antipsychotics, such as ziprasidone, exhibit binding profiles of low dopamine D2 receptor occupancy and high levels of postsynaptic serotonin (5HT2) blockade. This pharmacodynamic profile seems to result in a lower propensity for causing extrapyramidal symptoms. Thus, one might predict better tolerability of ziprasidone in HIV patients. 13

Furthermore, increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy (HAART), comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. 14 Therefore, an additional advantage of using ziprasidone in mania due to HIV is its purported neutral effect on diabetes and lipid profile, especially in those patients receiving HAART. 15

The authors’ rationale for initiating ziprasidone therapy via intramuscular route (in two of our three patients) was two-fold. First, oral administration of ziprasidone achieves a bioavailability of 60%, under fed conditions. In all of our patients, eating a meal with oral ziprasidone could not be guaranteed based on their manic condition. Thus, intramuscular ziprasidone essentially eliminated the risk of poorer absorption, as the bioavailability of intramuscular ziprasidone is 100%. Second, intramuscular ziprasidone offered a more “rapid acting” method of treating manic symptoms, such as agitation. 16

With a paucity of evidence to guide us, we began our patients on a standard antimanic dosage regimen (i.e., ziprasidone, 10 mg i.m. t.i.d. or 40 mg p.o. b.i.d.), ultimately discharging the patient on ziprasidone, 80 mg p.o. b.i.d. or t.i.d. While recognizing that our patients are a neuropsychiatrically vulnerable population, in a published series of 21 patients with HIV-related psychosis treated with risperidone, the mean maximum dose was 3.3 mg/day. 17 However, of their 12 manic patients, the average YMRS score was 28.36, while our patients’ had an average YMRS score of 34.3, thus the rationale for initiating ziprasidone therapy at standard antimanic dosages.

In conclusion, ziprasidone appears to be an effective treatment for acute mania caused by HIV. Advantages include a decreased risk of extrapyramidal symptoms (as compared to conventional antipsychotics), a lower propensity of metabolic complications in a patient population that relies heavily on a “medication cocktail” (i.e., HAART, that can increase the risk of metabolic complications), the option of intramuscular administration if symptoms of mania prevents oral administration, and finally, HIV patients have multiple levels of activation symptoms that may be helped by such an agent. Thus, the results of our case series support the need for further randomized control trials for ziprasidone in the treatment of mania due to AIDS.