HIV-1 infection superimposed on patients with an underlying diagnosed schizophrenia poses difficulties in anti-psychotic drug management for a number of reasons: a decrease in the vulnerability threshold to extrapyramidal side-effects (EPSE) due to the HIV-1-induced subcortical involvement (Lera & Zirulnik, Reference Lera and Zirulnik1999; APA Work Group on HIV/AIDS, 2000); interference with some antipsychotics in terms of cognitive function in patients with preexisting cognitive function impairment secondary to CNS infection; bone marrow toxicity secondary to combined treatment with an anti-psychotic plus an antiretroviral drug (Dettling et al., Reference Dettling, Muller-Oerlinghausen and Britsch1998); compliance, etc. Several alternatives have been suggested to overcome these serious side effects, though most of them systematically point to atypical anti-psychotic drugs as the treatment of choice in these cases (Della & Treisman, Reference Della and Treisman2005).

We present the case of a 30-year-old schizophrenic patient, with a history of a previous episode of schizophrenia one year before, who was admitted to the Acute Psychiatric Unit, Osuna Hospital (Spain), presenting acute confusional symptoms secondary to organic CNS HIV-related involvement. When symptoms of delirium had improved, active schizophrenic positive symptoms emerged: paranoid, megalomaniac ideas, auditory hallucinations, formal thought disorders (positive type), telepathic and xenopathic experiences, severe disorganized behavior. The patient was initially treated with ziprasidone 180 mg/day for 3 weeks, with a poor clinical response. Then, treatment with olanzapine 20 mg/day was introduced for an additional 3 weeks, with a similar poor response. The persistence of acute psychotic symptoms induced us to introduce clozapine treatment in an early stage, titrated up to 400 mg/day. The patient’s partial resistance to other atypical anti-psychotic drugs and the inhibitory activity exhibited by different clozapine metabolites in vitro on HIV-1 replication (Jones-Brando et al., Reference Jones-Brando, Buthod and Holland1997) were determinant in the early choice of this therapeutic alternative.

The patient presented a severe immune dysfunction on admission: 601 total lymphocytes/mm³ (reference range 1700–4000), CD4 26% (35–60%), CD8 38.2% (15–33%), CD4/CD8 ratio 0.5 (1.1–3.1), HIV viral load of 119,000 (reference value 0) and RNA log copies/ml 5.1 (reference value 0). The clinical picture showed an acute respiratory infection plus oral thrush, and the diagnosis of AIDS was made by the Infectious Disease Department.

The initiation of clozapine treatment reduced positive symptoms over the next 4 weeks (Andreasen Positive Symptoms initial score: 76, at 4th week: 27; Andreasen, Reference Andreasen1984). Improvement in the psychopathological status at 4 weeks of clozapine treatment allowed the patient to be competent so as to accept High Activity Antiretroviral Therapy (HAART) with tenofovir 300 mg/day + emtricitabine 200 mg/day + nevirapine 400 mg/day. The patient was then submitted to our Day-Psychiatric, low secure open unit. Follow-up of the patient was carried out (Psychiatric Day Unit plus Infectious Disease Department follow-up) during an additional 18 weeks, monitoring the hematological evolution on a weekly basis, liver and renal function every 2 weeks, lymphocyte sub-populations, psychopathological status, EPSE and cognitive function (MMSE every 4 weeks). No EPSE, hematological, renal or hepatic alterations were observed. Lymphocyte sub-populations evolved from the initial count of 601 total lymphocytes/mm³ (CD4/CD8 ratio 0.5) up to 2020 total lymphocytes/mm³ (CD4/CD8 ratio 0.6) at 18 weeks, with the viral load decreasing in the same period from 119,000 to 304 (log copies RNA/ml 2.48). Improvement of positive schizophrenic symptoms observed at week 4 of the initiation of clozapine treatment remained stable after an additional follow-up at week 18 (Andreasen Positive Scale score at this time: 23). The patient’s cognitive function presented an additional improvement at week 18, as measured by the MMSE-Spanish validated version (0–36 score; Lobo et al., Reference Lobo, Ezquerra and Gómez1979), increasing from 24 (initial score) to 34 (final score). No pharmacological side-effects of combined antiretroviral plus clozapine treatment were observed, there being neither anticholinergic effects nor seizures.

The favorable response to clozapine in this case could be supported by several explanatory hypotheses: firstly, several studies have highlighted the inhibitory activity on HIV-1 replication of different clozapine metabolites (Jones-Brando et al., Reference Jones-Brando, Buthod and Holland1997). In an assay on inhibition of virus-induced cytopathic effect (CPE), two metabolites of clozapine demonstrated antiviral activity, while other atypical or novel antipsychotics, as well as typical medications, had no effect. Based on ELISA, four additional metabolites inhibited the production of p24, the major internal HIV antigen (Jones-Brando et al., Reference Jones-Brando, Buthod and Holland1997). Other explanatory hypotheses could be postulated, such as the known immunomodulatory action exerted by some antipsychotic agents (Sperner-Unterweger, Reference Sperner-Unterweger2005), the halt in HIV-1 pathogenicity progression on the CNS due to new antiretroviral agents (HAART), or clozapine’s action on the 5-HT2A receptor, leading to the blocking of the subsequent entrance of some slow viruses, which use these neuronal receptors, into the cell (Altschuler & Kast, Reference Altschuler and Kast2005; Baum et al., Reference Baum, Ashok and Gee2003). Additional studies supporting these explanatory hypotheses are needed, but the multidisciplinary follow-up of schizophrenic patients with HIV-1, and the new treatments with high activity antiretroviral therapies (HAART) combined with atypical antipsychotic agents open up new horizons in the difficult management of these patients with comorbidity. This case-report suggests that it is important not to discount the use of a highly efficacious drug even in patients who are immune compromised, as the behavioral outcomes may outweighed the possible risks of agranulocytosis and further complications.