Table 1.

Pharmacological treatment in bipolar disorder and its impact on gut microbiota.

Drug	Therapeutic effect	Clinical evidence	Side effects	Main findings on gut microbiota	References
Risperidone	Antipsychotic Anti-manic	Risperidone is one of the first-line treatment during acute mania. It could be also an option in maintenance treatment	Metabolic disruption (moderate risk): weight gain, diabetes, metabolic syndrome, insulin resistance and cardiovascular disease	Decreased Akkermansia muciniphila Decreased gut microbiota diversity in women Altered Firmicutes/Bacteroidetes ratio Modifications in butyrate, propionate and tryptophan pathways	[13, 246, 249, 251, 252, 254]
Olanzapine	Antipsychotic Anti-manic	Olanzapine is one of the second-line treatment during acute mania, but it is also effective in maintaining and preventing also depressive episodes in BD-1	Metabolic disruption (high risk): weight gain, diabetes, metabolic syndrome, insulin resistance and cardiovascular disease. These side effects position olanzapine as a second-line treatment	Decreased Akkermansia muciniphila Decreased gut microbiota diversity in women Increased Firmicutes/Bacteroidetes ratio In rats, olanzapine modifies gut microbiota to an obesogenic bacterial profile It also proved to have antimicrobial activity in vitro against resident enteric bacterial strains	[13, 246, 250, 254]
Quetiapine	Antipsychotic Antidepressant in BD	First-line treatment for both maintenance and acute depression in BD-1 and 2	Metabolic disruption (moderate risk): weight gain, diabetes, metabolic syndrome, insulin resistance and cardiovascular disease	Increased Firmicutes/Bacteroidetes ratio Decreased Akkermansia muciniphila Decreased gut microbiota diversity in women	[246, 248, 254]
Aripiprazole	Antipsychotic Anti-manic	First-line treatment in acute mania and maintenance in BD-1. First-line treatment in agitation	Metabolic disruption (very low risk)	Decreased Akkermansia muciniphila Decreased gut microbiota diversity in women Increase bacterial richness and diversity (increase in Firmicutes phyla, Peptostreptococcaceae, Clostridiaceae and Ruminococcaceae family and in minor genera like Clostridium sensu stricto 1, Ruminiclostridium 5, Intestinibacter, Eubacterium coprostanoligens, Peptoclostridium, Eubacterium oxidoreducens, Christensenellaceae uncultured and Clostridia Family XIII, with a decrease in the relative abundance of Ruminococcus 1) Increase acetate and isovalerate production	[246, 254, 258]
SSRIs	Antidepressant Antimicrobial	As a second-line treatment, SSRI can be used as an adjunctive treatment for acute depression in BD-1. Specifically, sertraline can be used as a second-line treatment for acute depression in BD-2	Antidepressant therapy may have a potential risk of inducing modifications or resistances in gut microbiota There is a risk of manic switch or rapid cycling, so they should not be used in monotherapy	Antimicrobial and antifungal properties have been described. Some antidepressants showed to reduce Ruminococcus, Adlercreutzia and an unclassified Alphaproteobacteria. Interestingly, lower levels of Ruminococcus flavefaciens can relieve depressive-like behavior The effectiveness of antidepressants could be related to their antimicrobial effects	[13, 260, 261, 263, 366]
Lithium	Anti-inflammatory. Mood stabilizer	Mainstay of the prophylaxis in BD (first-line treatment for maintenance in BD-1 and -2). It can also be used in bipolar depression (first-line treatment in BD-1 and second-line in BD-2). Commonly used in combination with other drugs	Nausea, diarrhea, Weight gain, fine tremor, hypothyroidism, electrocardiogram anomalies, alterations in renal function and cognitive side effects	Increase bacterial richness and diversity in mice (enhance Actinobacteria growth and reduce Bacteroidetes, increasing the family of Peptostreptococcaceae, Clostridiaceae and Ruminococcaceae and the relative abundance of Clostridium sensu stricto 1, Ruminiclostridium 5, Intestinibacter, Eubacterium coprostanoligens, Peptoclostridium, Eubacterium oxidoreducens, Christensenellaceae uncultured and Clostridia Family XIII decreasing the relative abundance of Bacteroides and Ruminococcus 1 Expands Akkermansia municiphila Modulates expression of a receptor that mediates anti-inflammatory effects of the SCFA	[13, 243, 258, 265, 266]
Valproic acid	Mood stabilizer Anticonvulsant	First-line maintenance treatment in BD-1. Second-line treatment in BD-1 depression	Metabolic anomalies, including higher levels of insulin and triglyceride, weight gain and increased body mass index	Increase bacterial diversity and richness in mice (increase Actinobacteria and Firmicutes phyla along with a decrease in Bacteroidetes; Promote the growth of Peptostreptococcaceae, Clostridiaceae and Ruminococcaceae family, decrease the relative abundance of S24-7 uncultbact and enhance the relative abundance of Ruminococcaceae uncultured, Clostridium sensu stricto 1, Ruminiclostridium 5, Intestinibacter, Eubacterium coprostanoligens, Peptoclostridium, Eubacterium oxidoreducens, Christensenellaceae uncultured and Clostridia Family XIII Valproic acid can alter the biosynthesis of the fatty acid productions in some gut microbiota species	[13, 258, 268, 270]
Lamotrigine and carbamazepine	Mood stabilizer Anticonvulsant	It can be used during bipolar depression (first-line treatment in BD-1 and second-line in BD-2) and as maintenance treatment (first-line treatment in BD-1 and 2)		Lamotrigine and carbamazepine induce cytotoxicity in colonocytes and present antimicrobial effects: Lamotrigine showed to have a temperature-dependent activity inhibiting ribosome biogenesis in Escherichia coli and Salmonella enterica, exerting antimicrobial effects against Gram-positive Bacillus subtilis and Staphylococcus aureus Carbamazepine has antimicrobial effects on Gram-negative bacteria	[13, 271, 272]