Selective agonists of the sigma-1 (σ₁) ligand–operated chaperone protein, like igmesine or PRE-084, are antidepressants in preclinical depression models. σ₁-Protein activation may contribute to the antidepressant efficacy of drugs known to act as selective serotonin-reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors through direct or indirect involvement of the σ₁-receptor in the drug effect. We here compared antidepressant effects in two behavioral procedures, the forced swimming test (FST) and conditioned fear stress (CFS). The involvement of the σ₁-receptor was examined using a co-treatment with the σ₁-antagonist BD1047 or using σ₁-knockout (KO) mice. Igmesine but not PRE-084 decreased FST immobility. The SSRI fluoxetine and sertraline, but not fluvoxamine, and the tricyclic antidepressants imipramine, desipramine, and amitriptyline were also effective. Only the effect of igmesine was blocked by BD1047 or in σ₁-KO mice. Igmesine, PRE-084, fluvoxamine, and sertraline decreased the CFS immobility in a BD1047- and σ₁-KO–sensitive manner. Among tricyclics, only amitriptyline was effective and its effect was unaffected by BD1047 or in σ₁-KO mice. The behavioral effects induced by mixed σ₁-receptor/SSRI antidepressants, like fluvoxamine or sertraline, may therefore involve a non-selective action at both targets. Moreover, the CFS appears to more reliably uncover a σ₁ pharmacological component in antidepressant screening.