Due to a lack of controlled, prospective trials examining the pathophysiology and treatment of catatonia, current guidelines vary regarding how and when to best use antipsychotics in the presence of catatonia and what factors to consider in a thorough risk-benefit analysis. The literature is especially limited in describing the risks and benefits of using long-acting injectable antipsychotics in the presence of catatonia. We describe four cases where patients with preexisting catatonia received long-acting injectable first generation antipsychotics and experienced severe adverse effects (three experienced worsening of catatonia and one experienced neuroleptic malignant syndrome). The evidence base for managing comorbid catatonia and psychosis remains underdeveloped and inconsistent, but there are numerous known risk factors for adverse antipsychotic reactions, which we describe in relation to these cases. Finally, we present best practices to consider when managing comorbid psychosis and catatonia, especially when considering the use of long-acting injectable antipsychotics.