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While there is still much to be learned about depression in the context of HIV illness, studies over the past decade are generally reassuring. True, low-grade depressive symptoms are frequent among both HIV-positive and at-risk HIV-negative adults, but depressive disorders are the exception and not the rule, occurring in about 1 of 10 individuals. Similar to non-HIV populations, these depressive disorders are more likely to occur among those HIV-infected adults with severe personality problems, with a history of previous depressions, and with limited current social support. Although rates of depression may slightly increase with development of more severe physical symptoms, even then the clinician should not consider the presence of a depressive disorder as understandable, justified, and therefore "normal." Rather, depressive symptoms accompanied by suicidal ideation are signals for further evaluation and treatment. When antidepressant treatment is indicated, the weight of current evidence suggests that standard therapies can be safely and effectively prescribed for HIV-infected adults. For outpatients without severe physical illness, antidepressant medications are generally well tolerated in recommended dosages and do not increase immunosuppression. For those with more severe physical impairment, the adage for geriatric populations is applicable: "Start low and go slow." If lethargy and cognitive slowing is a major component of the depression, especially among those in later stages of disease, then psychostimulants may be helpful. When concerns about drug abuse preclude such a prescription, an activating antidepressant may be just as helpful to improve both mood and energy. For severe or refractory depressions, such as delusional affective disorders. ECT has been safely given to HIV-infected patients. And finally, accumulated clinical experience and a couple of systematic studies suggest that psychotherapy, alone or in combination with antidepressant drug therapy, can be remarkably beneficial. In sum, data support the fact that we have much to offer our depressed HIV-infected patients. Our task is to make sure that we identify their depressions when present and counter their feelings of hopelessness by ensuring that effective antidepressant treatments are provided.
The AIDS dementia complex (ADC) is one of the most common and important causes of morbidity associated with infection by human immunodeficiency virus type 1 (HIV-1). The evaluation of ADC in clinical trials is significant not only because of the clinical impact of this syndrome, but also because of the value of measuring its cardinal features as an index of drug efficacy and because of its emerging role as a major clinical end point. The objectives of therapy include both prevention of ADC in the presymptomatic patient and alleviation of established disease. At present, the pathogenesis of ADC is incompletely understood in several critical aspects, particularly the processes underlying the clinical manifestations of central nervous system (CNS) HIV-1 infection and, further, how such processes are related to systemic disease. Consequently, it is not yet clear to what extent, or in which patients, it is necessary to achieve "therapeutic" drug levels within the CNS. Nevertheless, the assessment of ADC prevention and treatment relies principally on the complementary approach of neurological examination for diagnosis and neuropsychological testing for quantitative serial measurement of treatment effects. Additionally, surrogate markers in cerebrospinal fluid (CSF) may hold promise for objective, rapid assessment of treatment response and dose adjustment. Other measurements, including more routine CSF analysis, neuroimaging, and neurophysiological assessments, are used principally for differential diagnosis rather than for monitoring ADC status. Accumulating experience with available antiviral agents suggests that ADC can be effectively prevented and treated, at least for some period of time, and that assessment of this condition is indeed a valuable approach for measuring antiviral therapy.
This chapter has summarized studies showing that cells of the immune system and glial cells of the CNS use many of the same cytokines as communication signals. Activated astrocytes and microglia are the principal sources of these cytokines in the CNS, although oligodendrocytes are capable of expressing IL-1 and TGF-beta. There is a complex circuitry of interactions mediated by cytokines, especially in the event of blood-brain barrier damage and lymphoid/mononuclear cell infiltration into the CNS. Infiltrating activated macrophages produce cytokines such as IL-1, TNF-alpha, and IL-6, which would trigger glial cells to produce their own cytokines. The activation of astrocytes and microglia to secrete proinflammatory cytokines such as IL-1, TNF-alpha, IL-6, and GM-CsF may contribute to the propagation of intracerebral immune and inflammatory responses initiated by immune cells, as well as enhancement of HIV-1 expression in the CNS. The cytokine cascades ongoing in the CNS could ultimately be suppressed due to the presence of immunosuppressive cytokines such as TGF-beta. Whether immune and inflammatory responses within the CNS are propagated or suppressed depends on a number of parameters, including (a) the activational status of these cells, (b) cytokine receptor levels on glial and immune cells, (c) the presence of cytokines with both immune-enhancing and immune-suppressing effects (IFN-gamma, IL-1, TNF-alpha, IL-6, TGF-beta, CsFs), (d) the concentration and location of these cytokines in the CNS, and (e) the temporal sequence in which a particular cell is exposed to numerous cytokines (see Fig. 1). The ultimate outcome of immunologic and inflammatory events in the CNS, as well as HIV expression, will be determined, in part, by an interplay of the above parameters.
This chapter has reviewed the current state of knowledge regarding the occurrence and possible role of oxygen radical generation and lipid peroxidation in experimental models of acute CNS injury. Although much work remains, four criteria that are logically required to establish the pathophysiological importance of oxygen radical reactions have been met, at least in part. First of all, oxygen radical generation and lipid peroxidation appear to be early biochemical events subsequent to CNS trauma. Second, a growing body of direct or circumstantial evidence suggests that oxygen radical formation and lipid peroxidation are linked to pathophysiological processes such as hypoperfusion, edema, axonal conduction failure, failure of energy metabolism, and anterograde (wallerian) degeneration. Third, there is a striking similarity between the pathology of blunt mechanical injury to CNS tissue and that produced by chemical induction of peroxidative injury. Fourth, and most convincing, is the repeated observation that compounds that inhibit lipid peroxidation or scavenge oxygen radicals can block posttraumatic pathophysiology and promote functional recovery and survival in experimental studies. Nevertheless, the significance of oxygen radicals and lipid peroxidation ultimately depends on whether it can be demonstrated that early application of effective antifree radical or antiperoxidative agents can promote survival and neurological recovery after CNS injury and stroke in humans. The results of the NASCIS II clinical trial, which have shown that an antioxidant dosing regimen with methylprednisolone begun within 8 hr after spinal cord injury can significantly enhance chronic neurological recovery, strongly supports the significance of lipid peroxidation as a posttraumatic degenerative mechanism. However, ongoing Phase III trials with the more selective and effective antioxidant U74006F (tirilazad mesylate) will give a more clear-cut answer as to the therapeutic importance of inhibition of posttraumatic free radical reactions in the injured CNS.
In summary, EAA play an important role in neurodegenerative disorders simply by virtue of the pathways in brain that utilize EAA as neurotransmitters. Thus, the striatum, which is so strikingly affected in Huntington's disease, receives massive EAAergic input from all regions of the cerebral cortex and from the thalamus. In Parkinson's disease, some of the key pathways projecting into the substantia nigra pars compacta and to the subthalamic nucleus and basal ganglia output zones also use EAA as neurotransmitters. In Alzheimer's disease, the cerebral cortex and hippocampus are dependent on EAAergic neurotransmission for normal function. Drugs that manipulate these neurotransmitter inputs and outputs could be very helpful in the symptomatic relief of all these neurodegenerative disorders. In addition, there may be secondary excitotoxic effects of EAA on neuronal function in neurodegenerative disorders. Genetic abnormalities may render subsets of neurons more vulnerable to changes in ion concentration or energy demands and thus more susceptible to EAA-induced neurotoxicity. Although EAA themselves may not be the primary culprit in a disease, EAA-induced toxicity may cause significant damage as a secondary phenomenon. If so, the neuronal damage could potentially be attenuated by the use of EAA antagonists. Future research on these problems hold great promise.
