Objective: Research suggests several possible associations among methamphetamine abuse, psychotic symptoms, depression, and posttraumatic stress disorder (PTSD), but the exact nature and clinical significance of these associations is unclear. Individuals who abuse methamphetamine increasingly present in hospital emergency rooms with acute psychiatric symptoms. The aim of this study was to identify patterns of depressive symptoms and explore predictors of acute versus sustained depressive symptoms in individuals who abuse methamphetamine and who have had psychotic symptoms. Methods: This longitudinal study, conducted in Vancouver, British Columbia, included 295 participants with methamphetamine use disorder who were seeking psychiatric help for depressive or psychotic symptoms, assessed at baseline and monthly for 6 months. Measures included substance use (including frequency, quantity, and route of administration), family history of psychosis and depression, trauma exposure, and PTSD symptoms. Results: Trajectory analyses on depressive symptoms revealed two profiles of depression: one with more severe and sustained depressive symptoms and one with decreasing and lower levels of depressive symptoms. Group comparisons showed that those with more severe and persistent depressive symptoms had more family history of depression ( p < .05), more years of alcohol and cocaine abuse ( p < .01), more traumatic events ( p < .001), and more PTSD symptoms ( p < .001). Logistic regression suggested that the strongest predictors of belonging to the high depression group were more severe psychotic symptoms at baseline (odds ratio [OR] = 2.03, p < .001), followed by quantity of methamphetamine used in the month preceding baseline (OR = 1.13, p < .05), severity of PTSD symptoms at baseline (OR = 1.07, p < .001), and the frequency of drug injection (OR = 1.25, p < .05). Conclusions: Our results are similar to those of other studies suggesting that depression and psychosis often coexist and that the intensity of methamphetamine abuse is linked to the severity of the depressive symptoms. The individuals who took part in this study had many coexisting problems, such as PTSD symptoms, polysubstance abuse, depression, and psychosis. In fact, depression, psychosis, PTSD, and substance abuse appeared to be intertwined in their development and expression. A more comprehensive treatment program to help individuals with multiple coexisting psychiatric and substance misuse issues is needed.