Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration

Table 1 Commonly used antipsychotic drugs and antidepressants, main mechanism of action and weight gain

Antipsychotic drugs	Main mechanism of action[23-25]	Main mechanism of action[28,29]	Weight gain[8,26,27]	Weight gain[31,32]
Typical APs
Chloropromazine	Blocks post-synaptic dopamine D2 receptors in the brain		+++
Haloperidol	Blocks post-synaptic dopamine D2 receptors in the brain		+
Thiothixene	Blocks post-synaptic dopamine D1, D2, D3, D4 receptors in the brain		+++
Fluphenazine	Blocks post-synaptic dopamine D1 and D2 receptors in the brain		+
Atypical APs
Clozapine	Blocks dopamine D2 and 5HT serotonin receptors in the brain		+++
Olanzapine	Blocks dopamine D1, D2, D3, D4 receptors, and serotonin 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor		+++
Quetiapine	Blocks dopamine D2 and serotonin 5HT2A receptors		+++
Ziprasidone	Blocks dopamine D2 and serotonin 5HT2A receptors		-/+
Risperidone	Blocks dopamine D2 and serotonin 5HT2A receptors		++
Aripiprazole	Partially agonizes dopamine D2, 5-HT1A receptors, blocks serotonin 5HT2A receptors		+
Paliperidone	Blocks dopamine D2 and serotonin 5HT2A receptors		+
Zotepine	Blocks dopamine D1, D2 and serotonin 5HT2A, 5HT2C, 5HT6 receptors		+++
Sertindole	Blocks dopamine D2 and serotonin 5HT2A, 5HT2C alpha-1 adrenergic receptor		+
Amisulpride	Blocks dopamine D2 and D3 receptors		+
Antidepressants
SSRIs
Sertraline		Increase serotonin 5HT level by blocking reuptake at presynaptic terminals		++
Fluoxetine
Excitalopram
Trazodone
Citalopram
Paroxetine
SNRIs
Duloxetine		Block serotonin and norepinephrine reuptake in the synapse, increase postsynaptic receptors’ stimulation		++
Venlafaxine
Levomilnacipran
Atypical ADs
Bupropion		Inhibits reuptake of dopamine and norepinephrine at the presynaptic cleft by binding to norepinephrine transporter and dopamine transporter		+
Mirtazapine		Increases release of norepinephrine into the synapse by blocking alpha-2 adrenergic receptors. Also antagonizes 5-HT receptor, increasing norepinephrine and dopamine		++
Viladozone		Enhances the release of serotonin across the brain’s serotonergic pathways specifically by inhibiting the serotonin transporter
Tricyclic ADs
Imipramine		Increase norepinephrine and serotonin concentration by inhibiting reuptake at the presynaptic neuronal membrane		+++
Nortriptyline
Amitriptyline
Doxepin
MAOIs
Phenelzine		Increase the levels of norepinephrine, epinephrine, serotonin, and dopamine by blocking reuptake of catecholamines and serotonin at the presynaptic neuronal membrane		++
Isocarboxazie
Tranylcypromine

APs: Antipsychotic drugs; ADs: Antidepressants; SSRIs: Selective serotonin reuptake inhibitors; SNRIs: Serotonin and norepinephrine reuptake inhibitors; MAOIs: Monoamine oxidase inhibitors; 5-HT: 5-hydroxytryptamine.

Table 2 Effect of psychotropic medications on the markers of de novo lipogenesis, gluconeogenesis and metabolic abnormalities in patients with psychiatric disorders

Parameters	Antipsychotic drugs	Antidepressants
De novo lipogenesis (markers)
SFAs	Increased[36,39]	Increased[58,61]
MUFAs	Increased[36,39]	Increased[58,61]
PUFAs1	Increased[36,39]	Increased[58,61]
Gluconeogenesis (precursors)
Lactate	Increased[125,126]	Decreased[128]
Citrate	Increased[129]	?
Pyruvate	Increased[129]	Increased[128]
Glutamate	Increased[129,130]	Increased[128]
Metabolic abnormalities
Blood glucose	Increased[72,121]	Increased[122,131]
IR/insulin level2	Increased[55,133]	Increased[65,74,75]
Triglycerides	Increased[8,55,56,72]	Increased[122]
Obesity (BMI)	Increased[8,55,72]	Increased[31,32,122]
Leptin	Increased[57,87]	Increased[132]
Adiponectin	Increased[55,89]	No change[65,134]
Resistin	Increased[55,89]	Reduced[134]
Diabetes	Increased[8,55,72]	Increased[5,65,74,135]
NAFLD	Increased[7,97,123]	Increase[95,96]

¹Polyunsaturated fatty acids are obtained through the diet, they are not synthesized via de novo lipogenesis in the body.

²Insulin resistance is a positively and strongly associated with de novo lipogenesis.

SFAs: Saturated fatty acids; MUFAs: Monounsaturated fatty acids; PUFAs: Polyunsaturated fatty acids; IR: Insulin resistance; BMI: Body mass index; NAFLD: Non-alcoholic fatty liver disease.

Table 3 Effect of selective adjunctive/anti-inflammatory drugs on symptoms of psychosis, depression, insulin resistance and non-alcoholic fatty liver disease

Agents/drugs	Psychosis1	Depression2	Insulin resistance3	NAFLD4
Aspirin	Reduced[136,137]	Reduced[142]	Reduced[151]	Reduced[160]
N-acetylcysteine	Reduced[136,137]	Reduced[143]	Reduced[152]	Reduced[161]
Minocycline	Reduced[136,137]	No change[144]	Reduced[153]	Increased[162]
Pregnenolone	Reduced[137]	Reduced[145]	?	Reduced[163]
Estrogens	Reduced[136,137]	Reduced[146]	Reduced[154]	Reduced[164]
Raloxifene	Reduced[137]	?	May reduce[155]	Reduced[165]
Curcumin	Reduced[138]	Reduced[147]	Reduced[156]	Reduced[166]
Pioglitazone	Reduced[139]	Reduced[148]	Reduced[157]	Reduced[167]
Celecoxib	Reduced[140]	Reduced[149]	Reduced[158]	Reduced[168]
w3-PUFAs	Reduced[141]	Reduced[150]	Reduced[159]	Reduced[169]

¹Measure of positive and negative syndrome scale score.

²Measure of Hamilton depression rating scale total scores.

³Measure of insulin resistance and hyperglycemia.

⁴Non-alcoholic fatty liver disease is positively associated with de novo lipogenesis; thus, reduced non-alcoholic fatty liver disease indicates a decrease in de novo lipogenesis.

NAFLD: Non-alcoholic fatty liver diseases; w3-PUFAs: w-3 polyunsaturated fatty acids.