Aim To study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients. Method Two hundred and five patients (111 males 54.1.% and 94 females 45.9%, mean age 10 months at the onset of epilepsy SD 1 year 1 month, range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments. Results Abnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ=−0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills. Interpretation A considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy. What this paper adds 5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.