Compositions, and methods of use thereof, are provided for the prevention or treatment of side effects associated with the use of drugs that act as 5HT2/5HT3 serotonin receptor antagonists and alpha-2 adrenergic receptor antagonists (5HT2/5HT3 antagonist/alpha-2 antagonist). The method involves using dopamine-releasing compounds, such as amantadine, anticonvulsants, such as zonisamide, or dopamine/norepinephrine reuptake inhibitors, such as bupropion, in combination with 5HT2/5HT3 antagonist/alpha-2 antagonists, such as mirtazapine, to reduce the excessive daytime drowsiness and/or weight gain associated with 5HT2/5HT3 antagonist/alpha-2 antagonist use for the treatment of disorders, such as, depression, schizophrenia, anxiety disorders, sleep-related breathing disorders, insomnia, migraine headache, chronic tension-type headache, hot flashes, lower back pain, neuropathic pain and functional somatic syndromes. Formulations of dopamine-releasing compounds or anticonvulsants with 5HT2/5HT3 antagonist/alpha-2 antagonists are provided. In particular embodiments, combination therapy with mirtazapine and zonisamide provides relief from chronic low back pain, while reducing or avoiding side effects associated with monotherapy with mirtazapine or zonisamide.