Novel methods are proposed for monitoring of therapeutic drugs which are present in plasma at extremely low concentrations. Many important drugs both exhibit wide-ranging effects and are present near or below the limit of detection of available analytical techniques. Gas chromatography/chemical ionization mass spectrometry (GC/CIMS) and gas chromatography/mass spectrometry/mass spectrometry (GC/MS/MS) provide the sensitivity and specificity needed for extremely low-level drug analysis, but equipment cost precludes their widespread use. This proposal concerns the development of GC/CIMS and GC/MS/MS techniques using the quadrupole ion trap (QUIT) for applications in trace-level drug analysis. The physical characteristics of the QUIT make it inherently suitable for such techniques. The mechanical simplicity of the instrument also reduces its cost far below standard GC/CIMS and GC/MS/MS instruments. These two techniques will provide lower detection limits and better discrimination against interfering compounds than standard gas chromatography/(electron ionization) mass spectrometry (GC/MS), currently the method of choice for trace drug analysis. Model compounds for this project are drugs used in psychiatric practice. These drugs are prime candidates for therapeutic monitoring because of their ability to simultaneously affect several systems within the brain. However, many are also present in plasma at levels near or below the limits of detection of available assay methods. The new techniques will first be demonstrated with the tricyclic antidepressants and antiepileptics, which can be measured by GC/MS. The low-level neuroleptics fluphenazine, fluphenazine decanoate, trifluoperazine, and thiothixene are present in plasma at concentrations too low to be measured reliably by GC/MS, and analysis of these compounds by the above techniques will be an essential step in understanding their function and more effective therapeutic use.