Table 2.

Potential contributors to pseudo-resistance in schizophrenia and depression.

	Schizophrenia	Depression
Drug plasma levels and adherence	Over one third of patients identified as ‘treatment resistant’ show evidence of poor adherence [23]	A cross-sectional study observed that 15% of patients with MDD presenting with poor clinical response to tricyclic antidepressant therapy had ‘unusually low plasma concentrations relative to dose’ [119]. Poor adherence is reported in 10–60% of patients with depression [24]
Genetic variants affecting trans-membrane transporters	P-glycoprotein transporter polymorphisms influence antipsychotic response in schizophrenia [120]	P-glycoprotein transporter polymorphisms predict treatment response in depression [121]
Genetic variants affecting liver drug metabolism	Both first-generation and second-generation antipsychotics plasma levels and/or efficacy reduced by some CYP1A2, 2D6 and 3A4 polymorphisms [122]	Ultra-rapid metabolizer capacity recognised with polymorphisms of certain CYP450 enzymes (e.g., CYP2D6 and CYP2C19) result in reduced plasma levels for several antidepressants, including TCAs, SSRIs and SNRIs, and influence clinical response [123]
Liver drug metabolism: influence of co-prescribed psychiatric medication	Co-prescription of psychiatric medications that act as CYP450 inducers (e.g., lamotrigine and carbamazepine) can reduce plasma levels of some antipsychotics [124]	Co-prescription of psychiatric medications that act as CYP450 inducers (e.g., lamotrigine, carbamazepine) can reduce plasma levels of some antidepressants, including TCAs, SSRIs and bupropion [125]
Liver drug metabolism: influence of co-prescribed physical health medication	Co-prescription of medications that act as CYP450 inducers (e.g., omeprazole, phenytoin, St John’s wort, rifampicin) can reduce plasma levels of some antipsychotics [122]	Co-prescription of medications that act as CYP450 inducers (e.g., St John’s wort, phenytoin) may reduce plasma levels of some antidepressants [126]
Tobacco smoking	Smoking reduces plasma levels of those antipsychotics metabolised via CYP1A2 (e.g., olanzapine, clozapine) [127]	Smoking reduces plasma concentrations of various antidepressants [128]
Sex	Male gender predicts lower plasma levels of some antipsychotics [129]	Male gender predicts lower plasma levels of some antidepressants [130]
Alternative Diagnosis	Symptoms of other disorders, such as bipolar affective disorder, obsessive compulsive disorder or autism spectrum disorder, may be mistaken for schizophrenia [31, 32]	A minority of apparently resistant unipolar depression may in fact be depression associated with bipolar disorder [33, 34]

Further evidence is provided in eTable 1.

TCA tricyclic anti-depressant, SSRI selective serotonin reuptake inhibitor, SNRI serotonin and norepinephrine reuptake inhibitor.