OBJECTIVES: To assess the impact of “equivalent substitution” (true generic of the prescribed drug) or “non-equivalent substitution” (switch to another agent, brand or generic) on perceptions, attitudes, and treatment adherence in patients with and without depression and anxiety disorder. METHODS: Over 10,000 randomly-selected US respondents from the 2007 National Health and Wellness Survey (NWHS) completed a self-administered, internet-based survey. The subpopulation of 2360 self-identified anxious/depressed respondents was supplemented with 5539 re-contacted self-identified anxious/depressed responders from the 2006/2007 NWHS. Responses from non-anxious/depressed patients were compared to those of self-identified anxious/depressed patients using t-tests, ANOVA, and multiple linear and logistic regressions. Comparisons were also made between anxious/depressed subgroups. RESULTS: A total of 52% of non-anxious/depressed patients experienced therapeutic substitution; 50% reported equivalent and 18% to non-equivalent substitutions (different brand - 10%, generic of another agent - 8%). 51% of the non-anxious/depressed and 71.5% of the anxious/depressed patients have experienced switching. More anxious/depressed patients found required step therapy unacceptable (P <0.001; many tried to change health plans for this reason.77% of non-anxious/depressed and 81% of anxious/depressed patients considered equivalent substitution (an equivalent generic) acceptable, but only about half in both groups thought that non-equivalent substitution was acceptable. Substitution affected attitudes and treatment adherence significantly more in anxious/depressed vs. non-anxious/depressed patients.  Importantly, anxious/depressed patients subjected to non-equivalent substitution reported significantly lower treatment adherence than those who were not (P <0.001).  Switching to a non-equivalent generic also reduced adherence more than switching to an equivalent generic (P<0.0001) in this population. CONCLUSIONS: About half of all respondents found required step therapy unacceptable. Anxious/depressed patients reported significant deterioration of treatment adherence and treatment-related attitudes following equivalent, and especially non-equivalent substitution. Substitution of prescribed drugs for depression or anxiety disorders negatively affected self-reported treatment adherence in the treated population, which may impact treatment outcomes.