In an article on HIV-related secondary mania in Uganda in this issue of the Journal, Nakimuli-Mpungu et al. report that among 141 patients who were admitted to a hospital over a 6-month period with first-episode acute mania and were eligible for the study and gave consent, 77 (55%) were HIV positive. Of these, 61 were diagnosed as having HIV-related secondary mania because they had no personal or family history of mood disorder. The 64 mania patients who were HIV negative were classified as having primary mania. The investigators found that patients with secondary mania were significantly older on average and had greater cognitive impairment than those with primary mania (Mini-Mental State Examination, mean=21.0, SD=3.8, versus mean=25.4, SD=2.0), even after controlling for education. In addition, patients with secondary mania were significantly more likely to have paranoid delusions, visual hallucinations, and auditory hallucinations. These findings demonstrate that first-episode mania in Ugandans well into adulthood is predictive of AIDS and are consistent with the hypothesis that HIV infection of the brain leads to the development of secondary mania. This formulation is also consistent with Mijch et al.’s (1) finding that antiretroviral drugs that penetrate the blood-brain barrier may be protective against secondary mania in persons with HIV infection. This study reminds us that the brain and its behavior are very sensitive indicators of many illnesses, including HIV/AIDS. Careful attention to nuances in the presentation of psychiatric illnesses, such as the Ugandan psychiatrists’ observation of first-episode mania occurring in adults who were older and more psychotic than expected for a first episode, can indicate the presence of other illnesses.
In the early 1970s, Robins and Guze (2) distinguished primary from secondary mood disorders. This distinction, along with the unipolar-bipolar distinction made by Perris (3), was the start of the process that led to our current subdivision of mood disorders into unipolar and bipolar disorders and those resulting from a medical condition (i.e., secondary mood disorders). Robins and Guze differentiated secondary from primary affective illness on the basis of whether the patient had any other psychiatric illnesses, previously or concurrently, and of the chronology of the associated causal condition in relationship to the development of the mood disorder (2). This early work, however, focused primarily on secondary depression.
The first report of secondary mania, by Krauthammer and Klerman in 1978 (4), established more stringent diagnostic criteria for secondary mania. These criteria included 1) a duration of at least 1 week, 2) elated or irritable mood, and 3) at least two of the following: hyperactivity, push of speech, flight of ideas, grandiosity, decreased sleep, distractibility, and lack of judgment. In addition, exclusionary criteria included a previous history of manic depressive or other affective illness and symptoms of a confusional state (such as delirium) co-occurring with the mania. Psychosis was not required for inclusion in this diagnostic category. Krauthammer and Klerman cited reports of cases of mania associated with use of medications, such as corticosteroids and isoniazid; metabolic disturbances, including those related to hemodialysis or a postoperative state; infections, such as influenza and St. Louis type A encephalitis; neoplasms, such as meningioma and spheno-occipital tumor; and epilepsy. Family history was negative in nine of their 10 reported cases. The median age at onset of secondary mania was 41 years, in contrast to that of primary mania, which was approximately 25 years.
Since that time, secondary mania has been reported to occur with virtually any disorder or process that disrupts brain structure or physiology, including tumors, degenerative dementias, traumatic brain injury, and stroke as well as a wide range of psychoactive medications. For example, one of the earliest reports of mania associated with stroke came from Cummings and Mendez in 1984, when they identified two cases of mania that occurred a few days after a right hemispheric thalamic infarction (5).
Although the goal of the article by Nakimuli-Mpungu et al. was to compare patients with primary mania and those with secondary mania associated with HIV, the obvious limitation is that HIV status was not held constant. Thus, two variables—primary versus secondary mania and positive versus negative HIV status—could influence the group comparison. The 16 HIV-positive patients who were diagnosed as having primary mania (i.e., those with a prior history of mood disorder) were excluded from the study. Thus, many of the findings from the secondary mania group in comparison with the primary mania group, such as greater cognitive impairment, higher frequency of paranoid delusions, greater frequency of visual and auditory hallucinations, and different scores on numerous items of the Young Mania Rating Scale, as well as the number of patients with a CD4 count below 200 and the number who lost a partner to HIV illness, are very likely related to HIV status, perhaps in combination with mania, rather than to differences between primary and secondary mania. On the other hand, numerous studies have reported an association between mania and HIV/AIDS, and this study adds to that literature as well as reinforcing the importance of late-onset mania as an identifying characteristic of AIDS in Uganda, where 1.4 million people are HIV positive.
One of the interesting findings to emerge from previously published small case series of patients with secondary mania is that many such patients seem to have more than one contributory factor (known as the two-hit hypothesis). For example, several years ago, using a two-by-two study design, our group (6) compared patients with and without mania after stroke and patients with and without the same brain lesion size and location. The study found that 60% of patients with primary mania had a family history of mood disorder, compared with only 27% of patients with secondary mania and 4% of nonmanic comparison subjects (Fisher’s exact test, p=0.0004). In addition to this lower rate of having a family history of mood disorder, which many studies have reported, we noted an association of mania with right hemispheric injury. In the secondary mania group, 82% had brain lesions involving the right basal temporal or orbital frontal cortex, basal ganglia, or thalamus. Furthermore, a comparison of patients with and without mania matched for lesion size and location found that patients with mania had subcortical atrophy as evidenced by increased ventricle-to-brain ratios of the bifrontal, bicaudate, and third ventricle (6). Remarkably, patients without subcortical atrophy had a positive family history of mood disorder and vice versa. Thus, each patient who had mania after stroke had a right hemispheric lesion connected with the limbic system and either genetic vulnerability or subcortical atrophy. Shukla et al. (7) found that patients with secondary mania had both traumatic brain injury and seizure disorders. Berthier et al. (8) found that secondary mania associated with stroke was associated with right hemispheric injury and a concurrent movement disorder. Thus, secondary mania may be a relatively rare disorder because more than one factor must be present to provoke the syndrome. In Nakimuli-Mpungu et al.’s study, it would be difficult to determine whether any secondary factors were present, because the study did not examine HIV-positive patients at comparable stages of infection who did not develop mania. One might speculate that a family history of mood disorder, right hemispheric limbic dysfunction, or premorbid environmental toxic exposure may have had a role in the development of secondary mania.
Although one cannot conclude from this study what specific characteristics differentiate HIV-induced mania from non-HIV-induced mania or why some patients develop mania after HIV infection while others do not, one real strength of Nakimuli-Mpungu et al.’s article is that it highlights the impact of the HIV/AIDS epidemic on mental health as well as physical health in sub-Saharan Africa. We are well aware of the need for preventive measures and medications to treat the HIV/AIDS epidemic in the region. This article demonstrates that there is also a tremendous need for mental health treatment.