Antidepressants or Metformin? The Undeniable Link between Metabolic Malfunction and Psychological Disorders

This article could very easily be a large book. That said, today I'm going to skim the surface of published research that ties blood sugar irregularity and insulin resistance with psychological disorders such as anxiety, depression, obsessive compulsive disorder, schizophrenia and bipolar disorder. 

Before we get into the data, I'd like to say that I hope what you read below further alleviates any stigma against psychological disorders. As you will see, psychological problems have been intrinsically tied to insulin resistance and just because insulin resistance is a very sly, secret and hidden destroyer of the human body and mind does not mean it's not there. I feel compelled to add that you do not have to be overweight to be insulin resistant. We so desperately need to illuminate, expose and fight the darkness of this shrouded supervillain. 

On that premise, insulin resistance is disguised because people are not being tested for it. Please read further about this in my article The HOMA-IR Test.

In an attempt to keep this article semi-condensed and organized, I will list the findings of three published studies for each of the five psychological conditions mentioned above.

Anxiety

The 2018 study Effect of Metabolic Syndrome on Anxiety in Mice found that "metabolic syndrome animals spontaneously developed anxiety-like behavior," and "GABA agonists (such as Valium and Gabapentin) partially reversed the metabolic syndrome-associated anxiety, suggesting a role for GABAergic pathway."  The study goes on to discuss the GAD65 (Glutamic Acid Decarboxylase) enzyme, which is critically involved in the regulation of GABA, a calming neurotransmitter. The presence of GAD65 antibodies are a hallmark indicator of type 1 or "autoimmune" diabetes, a serious condition in accordance with complete loss of insulin production. GAD65 antibodies can be present long before total systemic insulin loss, which I will go into another time. The study found that the loss of the GAD65 enzyme brought forth a "hyper-excitable brain primarily at the amygdala and hippocampal regions." These regions are associated with fear response, memory and learning, among other functions. A great deal of data exists correlating anxiety and other mental disorders with a loss of glutamate/GABA neurotransmitter harmony, or excitatory/inhibitory balance in the brain. What's not yet widely mentioned is what is at the core of this imbalance - insulin malfunction.

The 2016 paper Generalized Anxiety Disorder and Hypoglycemia Symptoms Improved with Diet Modification highlighted the case of a 15-year-old female who presented with generalized anxiety symptoms and hypoglycemia symptoms. Her diet consisted primarily of refined carbohydrates. The addition of protein, fat and fiber to her diet resulted in a substantial decrease in anxiety symptoms as well as a decrease in the frequency and severity of hypoglycemia symptoms. The study also found that a brief return to her previous diet caused a return of her anxiety symptoms, followed by improvement when she restarted the prescribed diet. It was concluded that: "This case strengthens the hypothesis that dietary glycemic index may play a role in the pathogenesis or progression of mental illnesses such as generalized anxiety disorder and subsequently that diet modification as a therapeutic intervention in the treatment of mental illness warrants further study."

An interesting 2018 study Neural, Hormonal, and Cognitive Correlates of Metabolic Dysfunction and Emotional Reactivity found a correlation between insulin resistance and hyperglycemia with a predisposition toward exacerbated emotional reactivity to negative stimuli. One of the study's authors, Dr. Auriel Willette of Iowa State University stated, "People with higher levels of insulin resistance were more startled by negative pictures. By extension, they may be more reactive to negative things in life. It is one piece of evidence to suggest that these metabolic problems are related to issues with how we perceive and deal with things that stress all of us out." Diabetic and pre-diabetic subjects also had poorer cognitive performance and cortisol abnormalities.

 Depression

The study The Antidiabetic Metformin as an Adjunct to Antidepressants in Patients with Major Depressive Disorder: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial published this year in Neurotherapeutics found metformin, the highly prescribed drug that lowers insulin resistance and increases insulin sensitivity, to be a "promising, effective, and safe short-term adjunctive approach in non-diabetic major depressive disorder patients." The article is $40 to fully access, so I will leave it here, but it's interesting that it's specifically stated to be effective in non-diabetic patients. As I've stated in previous articles, diabetes is the end-stage result of a long history of insulin resistance and metabolic disorder. Just because a patient is not classified as "diabetic" by current medical standards, does not mean that they are not affected by the numerous systemic damages of insulin resistance.  

The 2019 paper Insulin Resistance as a Shared Pathogenic Mechanism between Depression and Type 2 Diabetes noted that: "Due to the high resistant rate of anti-depressants, novel insights into the link between insulin resistance and depression may advance the development of alternative treatments for this disease," adding: "Data indicates that brain insulin resistance can impair physiological mechanisms of reward and learning that would ultimately elicit depressive symptoms...collectively, results suggest that brain insulin signaling dysfunction could impair the HPA (hypothalamic-pituitary-adrenal) axis normal response to stress, possibly facilitating the development of depression."

A 2015 study out of the Stanford University School of Medicine found that the insulin-sensitizing drug pioglitazone relieved symptoms of chronic depression in people previously resistant to treatment. "This is the first placebo-controlled study to show the antidepressant benefits of treating unremittingly depressed patients with an insulin sensitizing drug," the study's senior author, Dr. Natalie Rasgon, said. "This study is important," Rasgon continued, "because it bears out a hypothesis we first advanced over a decade ago about the connection between insulin resistance-the body's inability to efficiently process glucose, even with adequate insulin production in the pancreas- and mood disorders. While insulin resistance is more prevalent among people who are overweight or obese, significant numbers of people with normal weight are insulin resistant, too, but most don't find out about it until they're diagnosed with type 2 diabetes, hypertension or cardiovascular disease."

Obsessive-Compulsive Disorder

The 2019 study Converging Evidence Points Towards a Role of Insulin Signaling in Regulating Compulsive Behavior concluded that "our data indicates a role of abnormal insulin signaling in compulsive-like behavior," and "our experimental findings support our hypothesis that insulin-related pathways are involved in OCD etiology while also supporting an association between white matter integrity and compulsive behavior."

A study released in 2018 by the research group TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes) linked altered insulin signaling with compulsive-like behavior. An author of the paper, Dr. Jeffrey Glennon of University College Dublin, said: "We took large genetic data sets on OCD and did an analysis and what popped up was not glutamate but insulin. We thought there is something happening with insulin signaling. If you take the top gene from the insulin-signaling network and you knock it out, these animals show repetitive behavior like in autism or checking behavior like in OCD. They also show head tics analogous to Tourette's Syndrome."

The study Shared Genetic Etiology between Obsessive-Compulsive Disorder, Obsessive-Compulsive Symptoms in the Population, and Insulin Signaling, published in April 2020, identified "a shared genetic etiology between OCD, obsessive-compulsive symptoms (OCS) in the population and both central nervous system and peripheral insulin signaling." They concluded that: "Our results imply that altered insulin signaling is not only relevant for somatic disorders but is also involved in the etiology of psychiatric disorders and related symptoms in the population, especially OCD and OCS."

Schizophrenia

A book released in 2019 called Review on Biomarker Studies of Metabolic and Metabolism-Related Disorders contains a chapter titled Insulin Resistance in Schizophrenia. It states: "Schizophrenia and diabetes have been known to be linked disorders for decades. One reason is due to the fact that a major side effect of antipsychotic medication treatment is metabolic syndrome, which increases the risk of the patients developing type 2 diabetes and cardiovascular disorders. However, signs of metabolic syndrome in schizophrenia patients were identified more than 100 years ago, even before the development of anti-psychotic drugs. This suggests that schizophrenia itself predisposes towards diabetes and, in turn, insulin resistance may be a risk factor for the development of schizophrenia." 

The 2018 research article Hyperprolactinemia and Insulin Resistance in Drug Naive Patients with Early Onset First Episode Psychosis reveals that: "Hyperprolactinemia and glucose and lipid metabolism abnormalities are often found in patients with schizophrenia and are generally considered secondary to the use of antipsychotic drugs. More recent studies have shown these same neuroendocrine and metabolic abnormalities in antipsychotic naive patients with first episode psychosis, rising the hypothesis that schizophrenia itself may be related to an abnormal regulation of prolactin secretion and to impaired glucose tolerance." The article goes on to conclude that "hyperprolactinemia, increase in HOMA-IR, and psychotic symptoms may be considered different manifestations of the acute onset of schizophrenia spectrum psychosis, with a common neurobiological vulnerability emerging since adolescence."

The 2019 study Association of Insulin Resistance with Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatment reported that "schizophrenia polygenic risk is significantly associated with insulin resistance in first-episode, antipsychotic-naive patients with schizophrenia independent from selected demographic, lifestyle, and clinical factors. This result suggests that insulin resistance is a hallmark of schizophrenia rather than a secondary effect of emerging symptoms and supports the hypothesis that multiple susceptibility genes might exert pleiotropic effects co-occurring between the two conditions. Furthermore, the results indicate a potential association of insulin resistance with diminished response to antipsychotic treatment."

Bipolar Disorder

The 2019 study Metabolic Profile in Patients with Newly Diagnosed Bipolar Disorder and Their Unaffected First-Degree Relatives revealed that: "The prevalence of metabolic syndrome and insulin resistance is twice as high in patients with bipolar disorder compared with the general population," adding: "Our findings of elevated prevalence of metabolic syndrome and insulin resistance in patients with newly diagnosed bipolar disorder highlight the importance of screening for these conditions at an early stage to employ adequate and early care reducing the risk of cardiovascular disease and premature death."

Another 2019 study Impaired Glucose Metabolism in Bipolar Patients: The Role of Psychiatrists in its Detection and Management noted that: "Despite a growing body of evidence confirming the twofold influence of impaired glucose metabolism in bipolar disorder, it remains to be under-detected and undertreated. There are no guidelines concerning the coexistence of insulin resistance and bipolar disorder and no recommendations to screen affective patients for insulin resistance at an early stage of impaired glucose metabolism." The study's assessment of insulin resistance with HOMA-IR revealed insulin resistance in 51% of bipolar patients, and more than half of the insulin resistant patients had a fasting glucose result below 100mg/dL, which suggests that a simple assessment of fasting glucose is not sufficient to detect impaired glucose metabolism. The authors concluded that: "As the trajectory from dysglycemia to diabetes and its consequences may take many years and the process is reversible to some point, simple preventative measures and the earliest possible detection of impaired glucose metabolism may alleviate the psychiatric (poor course of illness, refractoriness to treatment, cognitive dysfunctions), as well as somatic consequences (increased risk of cardiovascular diseases and premature death)."

The 2015 study Insulin Resistance and Outcome in Bipolar Disorder disclosed that: "Little is known about the impact of insulin resistance on bipolar disorder," continuing with: "Patients with bipolar disorder and type 2 diabetes or insulin resistance had three times higher odds of a chronic course of bipolar disorder, three times higher odds of rapid cycling (from manic to depressive), and were more likely to be refractory to lithium treatment... Co-morbid insulin resistance may be an important factor in resistance to treatment in bipolar disorder."