A meta-analysis was carried out to evaluate data published between January 1974 and February 1998 comparing rates of treatment response and tolerability of pharmacological and psychological treatments for depression in persons over age 55. Drugs (tricyclic antidepressants, selective serotonin-reuptake inhibitors, and a mixed group of other drugs) were significantly better than placebo, with an average reduction in symptom severity of 48.0% versus 31.3% (analysis weighted by sample size; 50.6% vs. 21.4% unweighted). No single drug or group of drugs was superior in terms of efficacy, and no statistically significant differences in tolerability emerged between tricyclic antidepressants and selective serotonin-reuptake inhibitors, whether measured by total dropouts or by dropouts due to side effects. Compared to the data on pharmacological treatments, those for outcomes of psychological treatments are very limited. Existing data indicate that cognitive-behavioral, behavioral, and psychodynamic therapies are significantly better than placebo. In the current meta-analysis, response rates to these nondrug therapies did not differ significantly from those observed with tricyclic antidepressants or selective serotonin-reuptake inhibitors, but direct comparison data are insufficient for firm conclusions to be drawn about comparative efficacy. It is possible, even likely, that not only different subtypes of depression but also different patients vary in their treatment responses. However, lack of adequate data prevented the current meta-analysis from addressing these issues. Rigorously designed prospective studies on treatment outcome, taking into account the above differences, are urgently needed to provide robust data on which to base clinical recommendations for the treatment of depression in older patients.

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New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance.

The chloroethylating nitrosoureas (lomustine, fotemustine, cystemustine (BCNU) and methylating agents temozolomide (TMZ), dacarbazine (DTIC), procarbazine) have documented activity in metastatic malignant melanoma with single agent response rates of 15-25%. Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.

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