Table 8.

Summary of the clinical evidence of PPAR agonists in psychiatric disorders.

Disease	Target	Drug Name	Clinical Phase (Sample Size)	Main Findings/Primary Endpoint	Reference/Clinical Trial Identifier
Alcoholism	PPARα	Fenofibrate	II-completed (50)	▪ Primary endpoint: Visual Analog Scale of craving to drink and change from baseline in standard drinks per week	NCT02158273
		Gemfibrozil	II-terminated (3)	▪ Primary endpoint: Drinks per drinking day and percent days abstinent	NCT03539432
	PPARγ	Pioglitazone	II-terminated (16)	▪ Primary endpoint: Alcohol craving in response to the alcohol cue script, lipopolysaccharide challenge, and stress script	NCT01631630
Nicotine dependence/Smoking	PPARα	Gemfibrozil	II (27)	▪ No effect on abstinence, number of smoked cigarettes, and choice for non-nicotinized cigarettes	[245]
			II-completed (16)	▪ Decreased mean carbon dioxide exhaled ▪ Increased mean heaviness of smoking index	NCT02638597
		Fenofibrate	II (38)	▪ No difference in days quit, acute smoking reinforcement, and cue-inducing craving measurements	[246]
	PPARγ	Pioglitazone	I/II (42)	▪ Increased indicators of abuse potential ▪ Reduced measures of craving	[247]
Cocaine dependence	PPARγ	Pioglitazone	I/II (30)	▪ Reducing cocaine craving ▪ Improved fractional anisotropy values of white matter integrity	[248]
Opioid dependence	PPARγ	Pioglitazone	II (32)	▪ No effect on subjective, cognitive, analgesic, and physiological effects of oxycodone ▪ No reduction in drug craving and recreational drug use	[249]
			I (40)	▪ No effect on the prevention of opioid withdrawal symptoms ▪ Increased subjective opiate withdrawal scale score with higher need for rescue medications ▪ Did not reduce proinflammatory cytokines in cerebrospinal fluid or plasma	[250]
Bipolar disorder	PPARγ	Pioglitazone	IV (34)	▪ Decreased depressive symptoms ▪ Improved self-reported depressive symptoms and clinician-rated anxiety scores ▪ Improved cognitive functions and insulin sensitivity	[251]
			IV (38)	▪ No difference in depressive symptoms, response, and remission rates ▪ No change to mania scores, metabolic and inflammatory markers	[256]
			III-ongoing (60)	▪ Primary endpoint: Change in the clinical condition	EUCTR 2014-003803-31
		Rosiglitazone	NA-completed (12)	▪ Decreased depression severity scoring	[252]
	PPARα	Bezafibrate	II-ongoing (30)	▪ Primary endpoint: Change in Montgomery-Åsberg Depression Rating Scale	NCT02481245
Major depressive disorder	PPARγ	Pioglitazone	II-completed (23)	▪ Primary endpoint: Change in Depression Symptom Severity	NCT00671515
			II/III (50)	▪ Improved depression severity score ▪ Led to earlier improvement with better treatment response ▪ Higher remission achieved in pioglitazone group	[253]
			IV (37)	▪ Significant difference in mean decrease of depression scores in insulin resistant subjects ▪ Younger patients with insulin resistance had a greater decline in depression scoring	[254]
Schizophrenia	PPARγ	Pioglitazone	IV (56)	▪ Reduced fasting glucose and high density lipoprotein ▪ Reduced depression symptoms scores, but not cognitive performances ▪ Subjects from China had no improvement in metabolic parameters and psychopathology scorings	[255]
Autism spectrum disorder	PPARγ	Pioglitazone	NA (25)	▪ Reduced aberrant behaviors like irritability, lethargy, stereotypy and hyperactivity	[257]
			II (44)	▪ Reduced irritability, lethargy/social withdrawal, and hyperactivity scores	[258]
			II (25)	▪ Improved behavior scores in global function, social function, irritability, hyperactivity, repetitive behaviors, and anxiety ▪ Decreased IL-6 ▪ Increased IL-10	[259]