Psychosis
Isotretinoin has also been linked to psychosis. Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms. The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia. The evidence for this is threefold: transcriptional activation of the dopamine D2 receptor – in addition to serotonin and glutamate receptors – is regulated by retinoic acid; schizophrenia and the retinoid cascade have been linked to the same gene loci; and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia. Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid. Musculoskeletal
Isotretinoin has a number of muscoloskeletal effects. Myalgia (muscular pain) and arthralgia (joint pain) are rare side effects. Retinoids, such as high dose etretinate, are well known to cause bone changes, the most common type of which is hyperostotic changes (excessive bone growth), especially in growing children and adolescents. Other problems include premature epiphyseal closure and calcification of tendons and ligaments. The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using X-ray imaging. Gastrointestinal
Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea and abdominal pain.
In March 2018, European Medicines Agency issued a warning on a possible risk of neuropsychiatric disorders (such as depression, anxiety and mood changes) following the use of oral retinoids, including isotretinoin, though the limitations of the available data did not allow them to clearly establish whether this risk was due to the use of retinoids.In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression and suicide, as well as articles related to class effect, dose response, and biologic plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals. Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin. However, whether isotretinoin use is causally associated with mental illness remains controversial.Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive challenge/dechallenge/rechallenge with isotretinoin, involving administering isotretinoin, withdrawing the drug, and then re-administering it. The majority of these cases had no psychiatric history. There is also a temporal relationship between the development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment. Further, higher doses of isotretinoin increase the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses. Studies have uncovered several biological processes which may credibly explain the affective changes induced by isotretinoin.