Metformin (Glucophage®, Fortamet®, Glumetza®, Riomet®), currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes, is a fascinating drug that has various cellular and molecular mechanisms (Viollet et al., 2012). Some of these mechanisms may explain its ability to lower glucose levels in patients with diabetes. Different metformin mechanisms have also been invoked to explain or justify other off-label clinical and investigational uses: diabetes prevention in high-risk patients, polycystic ovary syndrome, non-diabetic obesity, non-alcoholic fatty liver disease, and prevention or treatment of cancer (Scarpello & Howlett, 2008). In recent years, there has been considerable interest in studying the use of this drug in psychiatric patients, and I will review some of this work in this article.
Historical Development and Use of Metformin
The perennial herb Galega officinalis (G. officinalis) has been used medicinally to treat a variety of conditions, including diabetes (Bailey & Day, 2004). Studies conducted in the late 1800s found that G. officinalis contained high concentrations of the chemical guanidine, which was subsequently shown to have glucose-lowering effects in animals. The glucose-lowering biguanide drug dimethylbiguanide was synthesized in 1929, but it was not until the 1950s that Jean Sterne and his colleagues conducted clinical development studies investigating its anti-diabetic properties in humans. He proposed the name “Glucophage” (“glucose eater”) for this particular drug. Two other biguanide drugs (phenformin and buformin) were synthesized and investigated in clinical studies in the late 1950s. All three drugs were used clinically during the 1960s and into the 1970s, but phenformin and buformin were used more often than dimethylbiguanide because of their greater potency.
Phenformin was especially prone to causing lactic acidosis, with a high mortality rate. For this reason, it was eventually withdrawn from most countries (including the U.S. market by the FDA in 1978), but is still available in some countries and is still being investigated in cancer research. Buformin (never marketed in the United States) was also associated with lactic acidosis and was eventually withdrawn from many countries in the 1970s, but is still available in a few countries. Dimethylbiguanide, commonly known as metformin, was better tolerated and less prone to causing lactic acidosis. Metformin was used clinically outside of the United States, finally supplanting phenformin and buformin when they were withdrawn from most countries. It was not approved by the FDA as a treatment for type 2 diabetes mellitus until 1994, but it is the most commonly prescribed drug for diabetes around the world (Viollet et al., 2012).
Metformin, Weight Gain, and Metabolic Abnormalities
Metformin normalizes blood glucose levels by decreasing hepatic glucose production, decreasing intestinal glucose absorption, increasing peripheral tissue uptake of glucose, and increasing peripheral insulin sensitivity. Metformin is associated with modest weight loss among non-diabetic and diabetic obese patients, including children and adolescents (Al-Shareef, Sanneh, & Aljoudi, 2012; Bouza, Lopez-Cuadrado, Gutierrez-Torres, & Amate, 2012). Metformin has also been demonstrated to have positive effects on various metabolic abnormalities associated with cardiovascular disease in obesity and diabetes (Scarpello & Howlett, 2008). Because patients with chronic psychiatric illness have high rates of overweight and obesity, as well as increased rates of weight-related diabetes and heart disease, metformin has been advocated for use among these patients (Curtis, Newall, Myles, Shiers, & Samaras, 2012; Taylor, 2012). At least 11 controlled studies have been published reporting on the use of metformin for patients with chronic psychiatric illness taking various antipsychotic drugs (C.H. Chen et al., 2013; Jarskog et al., 2013; Newall et al., 2012; Wu et al., 2012). These trials and other uncontrolled studies have generally found metformin to be effective, well tolerated, and safe for preventing or treating antipsychotic-related weight gain and for improving metabolic abnormalities in these patient populations. Metformin was also shown to be effective in reversing antipsychotic drug-induced amenorrhea, weight gain, and insulin resistance in women with schizophrenia (Wu et al., 2012).
Is There A Role for Metformin In The Treatment of Depression or Other Psychiatric Disorders?
The hippocampus has a central role in learning and memory, and it is a key regulatory structure within the limbic system. Major depression is characterized by structural and neurochemical changes in various limbic system structures, including the hippocampus, that regulate mood and cognitive functions.
Cognitive impairment is a consistent finding in depressed patients but is also commonly seen among patients with other psychiatric disorders. Imaging studies of patients with severe depression, schizophrenia, or post-traumatic stress disorder (PTSD) have demonstrated hippocampal atrophy in subgroups of these patients. Adult neurogenesis is the process of generating functional neurons from neural stem cells in the adult brain (Lee, Reif, & Schmitt, 2013). Neurogenesis does not occur in all brain regions but has been documented within the hippocampus in animal studies and in some human studies. Disturbed adult neurogenesis is associated with depression-like behavior and cognitive deficits in animal models. Various antidepressant therapies, including antidepressant drugs, enhance hippocampal neurogenesis in animals. Hence, disturbed neurogenesis, affecting the hippocampus, may contribute to the cognitive deficits and reduced hippocampal volumes seen in depressed patients.
Metformin’s ability to suppress hepatic glucose production is linked to its effect on activating the enzyme AMP-activated kinase (AMPK), which initiates a signaling cascade in liver cells. When metformin activates AMPK, AMPK phosphorylates the enzyme atypical protein kinase C (aPKC). In turn, aPKC then stimulates the phosphorylation of CREB binding protein (CBP). The protein CBP is ubiquitously expressed in different cell types throughout the body, and it may have an important role in neurogenesis. Based on this premise, a recent study investigated the effect of metformin on neurogenesis (Wang et al., 2012). These investigators demonstrated that metformin was able to promote rodent and human neurogenesis in cultured neural stem cells. They also demonstrated that giving metformin to adult mice stimulated hippocampal neurogenesis, and these mice showed enhanced spatial memory formation.
In another recent animal study of rats fed a high-fat diet, administration of metformin (compared to placebo administration) prevented brain mitochondrial dysfunction and completely restored learning behavior, which were impaired by a high-fat diet (Pintana, Apaijai, Pratchayasakul, Chattipakorn, & Chattipakorn, 2012).
Because diabetes is associated with cognitive impairment and depression, and depression is a risk factor for developing diabetes, disturbed hippocampal neurogenesis has been suggested as a way to understand this reciprocal relationship (Ho, Sommers, & Lucki, 2013). In a retrospective case-control study, Wahlqvist et al. (2012) found that individuals taking metformin and a sulfonylurea drug (a class of anti-diabetes drugs) had a lower incidence of depression compared to individuals not taking anti-diabetes drugs. However, in a 6-week double-blind study of obese non-diabetic young women (approximate mean age = 20) with polycystic ovary syndrome and mild comorbid depression, Kashani et al. (2013) found that metformin had no effect on depression symptoms compared to the anti-diabetes drug pioglitazone (Actos®).
Experimental studies using metformin in animal models of Alzheimer’s disease have been conducted (Hsu, Wahlqvist, Lee, & Tsai, 2011; Imfeld, Bodmer, Jick, & Meier, 2012). Some animal studies have found that metformin decreases or attenuates Alzheimer’s disease–like neuropathological changes. One animal study demonstrated that metformin administered alone increased the generation of beta-amyloid peptides (a notable finding in Alzheimer’s disease), but that beta-amyloid levels were reduced when metformin was administered together with insulin (Y. Chen et al., 2009). In humans, a post-mortem case-control study suggested that insulin combined with other anti-diabetes medication was associated with less Alzheimer’s disease neuropathology (Beeri et al., 2008), although metformin was not singled out in their analysis. In a population-based case-control study, Imfeld et al. (2012) found that long-term use of anti-diabetes drugs or insulin was not associated with a decreased risk of developing Alzheimer’s disease but that there was a suggestion of a slightly higher risk of Alzheimer’s disease in long-term metformin users. By contrast, in a population-based observational cohort study, Hsu et al. (2011) found the incidence of dementia was increased in type 2 diabetes and reduced by the use of sulfonylurea drugs or metformin.
Clinical Use of Metformin
The FDA-approved metformin dose range (for its labeled indication) is 1,000 to 2,550 mg per day, and the same dosage range has been used in the studies investigating its use for antipsychotic drug–related weight and metabolic adverse effects. Metformin is typically given in a divided dose twice daily (immediate release) or once daily (extended release).
Metformin absorption is enhanced with food, so it is usually taken with meals. It is not metabolized by the liver and is not associated with hepatic drug-drug interactions. Because metformin is excreted through the kidneys, it is contraindicated in patients with significant renal disease. Cimetidine (Tagamet®) decreases the excretion of metformin, resulting in higher concentrations; therefore, lower doses should be used. Metformin should be stopped temporarily in patients receiving intravenous contrast dyes for imaging studies, because of their renal effects.
Common adverse effects of metformin include diarrhea, dyspepsia, nausea, intestinal gas, malaise, and headache. It can decrease the absorption of vitamin B12, and B vitamin supplementation should be recommended. Hypoglycemia rarely occurs, as it does not increase insulin production. Metformin ordinarily inhibits hepatic lactate uptake and the conversion of lactate to glucose. Lactic acidosis is a potentially serious, but very rare, adverse effect. Signs and symptoms of lactic acidosis include severe nausea and vomiting, abdominal pain, and tachypnea (rapid breathing). Lactic acidosis is mainly seen in cases of metformin overdose, in patients with severe renal insufficiency or hepatic insufficiency, with excessive or chronic alcohol use, with severe dehydration, and in very elderly patients (older than 80). Drugs or medical conditions that cause a metabolic acidosis can also potentially increase the risk of metformin-associated lactic acidosis. For such a widely prescribed drug, metformin has an excellent safety and tolerability profile (Scheen & Paquot, 2013). Studies cited previously found it to be equally safe and well tolerated in psychiatric patients.
Metformin is an old, but interesting drug. Based on the findings from many studies, it deserves greater off-label use for preventing or treating psychotropic drug-associated weight and metabolic adverse effects. The potential effect of metformin to induce hippocampal neurogenesis is especially exciting. Additional studies of metformin are warranted in patients with mood or cognitive disorders. For example, metformin could be investigated as an add-on drug, together with antidepressant medications or other antidepressant therapies, to determine whether it improves mood and cognitive impairment in chronic treatment resistant depression. Nurses are likely to see patients taking metformin and should be familiar with its use, given the potential future use of this drug for other clinical purposes.
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