The COVID-19 pandemic has led to an increase in psychological distress in the general population, but contrasting results have been shown regarding its impact on psychological symptoms in clinical and non-clinical samples. Consequently, the aim of the present study was to compare in a longitudinal design (September-November 2020 and February-April 2021) the mental health outcomes of a clinical and a control sample and to determine the implications of various risk and protective factors in this regard. A total of 234 participants from the general population and 80 psychiatric patients took part in the present online study using the following measurements: the Brief Symptom Checklist (BSCL); Three-Item Loneliness Scale (TILS); Resilience Scale-13 (RS-13); and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale-Non-Illness (FACIT-Sp Non-Illness). The results show an overall decrease in active suicidal ideation as well as "peace", a subscale of spiritual well-being, as well as increases in passive suicidal activation in the clinical sample, which did not change in the control sample. Psychological symptoms did not significantly change in either group. Significant group effects show an increase in resilience in the clinical sample. Resilience and peace turned out to be protective factors for negative mental health outcomes. However, loneliness, which interestingly increased only in the control sample, was shown to be an overall potential risk factor. Our results highlight the complex implications of the COVID-19 pandemic on the mental health outcomes of different groups in the population, demonstrating the necessity of further research, specifically regarding the risk of active and passive suicidal activation. Highlighted protective factors are discussed in regards to spirituality (i.e., peace), which is not strictly related to religion but rather personal spirituality related to the meaning of situations of one's life, as well as in terms of mental health interventions.