Major depressive disorder (MDD) is a significant global public health concern, affecting over 264 million individuals worldwide. Antidepressant medications are frequently prescribed as the first-line treatment option for moderate to severe MDD and anxiety disorders. However, most antidepressants have numerous documented adverse events, including cardiometabolic effects and weight gain, which are major public health concerns. Weight change is common when you start taking antidepressants. Typically, that means weight gain. But in some cases, antidepressants may trigger weight loss and a lower number on your scale.
This article presents a critical evaluation of the published reports on the mechanisms underlying antidepressant-induced weight gain, comparative effects across drug classes, and mitigation strategies.
The Prevalence and Impact of Antidepressant-Induced Weight Gain
Antidepressants are widely prescribed for major depressive disorder and anxiety, yet their long-term use is associated with weight gain, affecting up to 55-65% of patients. This adverse effect contributes to treatment discontinuation, relapse, and worsened metabolic health outcomes, including increased risk for obesity and type 2 diabetes. Weight gain associated with antidepressant use is an important clinical consideration, as it can negatively impact treatment adherence and overall health outcomes. Patients who experience weight gain may discontinue or avoid treatment, increasing the risk of relapse or worsening depressive symptoms. Moreover, antidepressant-induced weight gain can exacerbate comorbid conditions such as obesity, diabetes, and cardiovascular disease. Obesity is two to three times more prevalent in individuals with psychiatric disorders, and long-term antidepressant use has been linked to an increased risk of metabolic disorders. Given that obesity is the second most common cause of preventable death after smoking, the need to monitor and mitigate antidepressant-induced weight gain is vital.
Types of Antidepressants and Their Mechanisms of Action
There are multiple classes of antidepressants, each with different mechanisms of action. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are typically considered first-line treatments for MDD. However, the selection of an antidepressant should be individualized based on prior treatment response, adverse effect profiles, and patient preference.
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs, such as fluoxetine, sertraline, and citalopram, act by inhibiting the serotonin transporter (SERT), leading to increased serotonin levels in the synaptic cleft and enhanced serotonergic neurotransmission.
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Tricyclic Antidepressants (TCAs)
TCAs, such as amitriptyline and nortriptyline, inhibit both SERT and NET but also interact with histaminic, cholinergic, and alpha-adrenergic receptors, expanding their side effect profile. Because of this, TCAs are typically reserved for treatment-resistant depression.
Monoamine Oxidase Inhibitors (MAOIs)
MAOIs, such as phenelzine, prevent the breakdown of serotonin, norepinephrine, and dopamine via inhibition of monoamine oxidase enzymes. While effective, MAOIs, like TCAs, are generally used as a last resort due to dietary restrictions and potentially severe drug interactions.
Atypical Antidepressants
Atypical antidepressants, such as bupropion and mirtazapine, have unique mechanisms. Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) with less effect on serotonin compared to other antidepressants. It is often prescribed to those experiencing sexual dysfunction with SSRIs or for smoking cessation.
Neurochemical Pathways Linking Antidepressants to Weight Gain
The relationship between antidepressant use and weight gain is complex, as underlying psychiatric conditions such as depression could involve changes in appetite, physical activity, and energy metabolism. Antidepressant-induced weight occurs through alterations in neurotransmitters, metabolic regulation, and behavioral changes. Current findings suggest the role of histamine and serotonin off-target appetite-promoting pathways in adverse weight-gain effects.
Serotonergic Pathways
Serotonin (5-hydroxytryptamine [5-HT]) has a range of effects in central and peripheral nervous systems. Interestingly, the highest concentration of serotonin is found in the GI tract’s enterochromaffin cells. Here, serotonin functions to increase intestinal mobilization through stimulation of myenteric neurons, enhancing digestive processes while also reducing appetite. In the CNS, serotonin plays a role in mood, sleep, and appetite. Beyond appetite regulation, serotonin in the CNS has a significant impact on mood. Its absence is associated with depression, anxiety, and manic episodes.
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Serotonin is synthesized from the amino acid tryptophan, which is first converted into 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase (TPH) and then into serotonin via aromatic acid decarboxylase. These reactions occur in the raphe nuclei of the brainstem, where serotonin is also released. Serotonin from the rostral nuclei of the serotonergic system regulates various functions, such as temperature, appetite, sleep cycles, emesis, and sexual behavior. These functions are mediated by different serotonin receptors.
The DRN serotonergic neurons suppress appetite through multiple mechanisms, including innervation of the mediobasal hypothalamus. Additionally, the DRN can decrease appetite via projections to the lateral hypothalamic area (LHA) and the bed nucleus of the stria terminalis (BNST). Serotonergic neurons also stimulate GABAergic neurons in the rostral zona incerta and paraventricular thalamus to inhibit appetite. DRN serotonergic neurons maintain reciprocal connections with other brain regions, including the paraventricular nucleus of the hypothalamus (PVH), lateral hypothalamic area (LHA), arcuate nucleus (ARH), central amygdala (CeA), and parabrachial nucleus (PBN). A recent study demonstrated that activating the DRN serotonergic pathway to the ARH lead to a decrease of food intake via depolarization of anorexigenic proopiomelanocortin (POMC) neurons while simultaneously hyperpolarizing orexigenic agouti-related peptide (AgRP) neurons.
Different serotonin receptor subtypes have varying effects on food intake. Activation of 5-HT2ARs and 5-HT2CR reduces food intake, whereas 5-HT2BR activation increases it. 5-HT2CR agonists stimulate POMC neurons through phospholipase C (PLC) signaling. Other, less studied serotonin receptors also influence appetite. 5-HT3R activation increases appetite and food intake in the nucleus accumbens (NAc) but has the opposite effect in the ventral tegmental area (VTA) and nucleus of the solitary tract (NTS). Activation of 5-HT4Rs in the NAc decreases food intake through increased expression of CART mRNA. On the other hand, 5-HT6 increases food intake in the NAc, while 5-HT7 has the opposite effect.
SSRIs and Weight Gain
SSRIs are commonly associated with weight gain. They increase serotonin levels in the synaptic cleft by reducing its reuptake via serotonin transporters in the presynaptic neuron. Given serotonin’s role in the CNS, it would be expected that SSRI use would lead to decreased appetite and food intake. However, more recent studies have shown that chronic SSRI use (≥1 year) is associated with weight gain.
Several mechanisms have been proposed to explain SSRI-induced weight gain. One mechanism involves serotonin receptor modulation. Long-term fluoxetine (Prozac) use has been shown to downregulate brainstem serotonergic neurons through autoinhibitory signaling via 5-HT1RA. Over extended treatment periods, there is also a decrease in 5-HT2 receptor expression and activity, leading to reduced phosphorylation of CREB and STAT3, along with decreased POMC expression in hypothalamic neurons. This ultimately results in increased food intake and body weight. Additionally, 5-HT2 receptor desensitization may contribute to weight gain. Studies have shown that pretreatment with 5-HT2 antagonists prevents the anorexic effects of d-fenfluramine (DFF), suggesting that SSRIs that desensitize or downregulate 5-HT2C over time could contribute to increased appetite and weight gain. Supporting this, 5-HT2A receptor agonism promotes satiety, while inhibition leads to increased food intake and weight gain. Furthermore, 5-HT2C receptor antagonism has been associated with glucose intolerance, indicating that long-term SSRI or TCA use, which also affects these receptors, may contribute to insulin resistance and weight gain. Another proposed mechanism involves the inhibition of dopamine pathways in the striatum, which can lead to reduced energy expenditure and weight gain.
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Dopaminergic Pathways
Food acquisition requires the recognition of rewarding stimuli, and in addition to the serotonergic pathway, the dopaminergic pathways have also been implicated in these processes. Dopamine plays a key role in the reward aspects of feeding through dopaminergic projections from the ventral tegmental area (VTA) to the NAc. The dopaminergic mesolimbic pathways are essential for feeding behaviors, and disruptions in these pathways can lead to changes in food intake. Dopamine release in the NAc has been observed during feeding, food anticipation, and in response to food-related stimuli. Additionally, certain metabolic hormones, such as ghrelin and leptin, can act directly on the VTA to influence feeding behavior. Leptin administration in the VTA has been found to inhibit dopamine activity, leading to a decrease in food intake. In contrast, ghrelin, which is secreted from the stomach and has receptors in the mesolimbic circuits, has the opposite effect-it enhances dopamine release and activity in the VTA, promoting food intake.
TCAs, which primarily act on dopamine and histamine receptors, have also been associated with weight gain. TCAs inhibit H1 histamine and muscarinic acetylcholine receptors, both of which have been linked to increased food intake and weight gain.
Metabolic Changes and Insulin Resistance
Psychotropic medications are associated not only with weight gain but also with metabolic changes such as diabetes and dyslipidemia. Antidepressant use has been linked to changes in insulin resistance, with various antidepressants, including SSRIs, TCAs, and mirtazapine, implicated in the development of these metabolic disorders. Many commonly used antidepressants can lead to insulin resistance (IR) in individuals with and without type 2 diabetes mellitus (T2DM). Long-term antidepressant use has correlated with an increased risk of T2DM. A case-control study in the United States found that antidepressant use greater than 24 months at moderate-to-high daily doses was associated with an increased risk of developing T2DM compared to non-users. A 2023 study analyzing the response to vortioxetine, an SSRI, found a significant increase in insulin resistance following treatment. This study also indicated that increased IR contributed to treatment nonresponse and elevated C-reactive protein (CRP) levels, underscoring the metabolic effects of antidepressant therapy.
TCAs may also influence insulin secretion through their inhibitory effects on M3 muscarinic receptors, which play a key role in insulin release. Notably, antipsychotics that antagonize M3 receptors, such as clozapine, have been associated with the development of T2DM due to decreased insulin secretion. Some TCAs, such as desipramine, have been linked to increased insulin resistance and hyperglycemia.
Comparative Weight Effects Across Antidepressant Classes
Weight gain varies significantly by antidepressant class. Tricyclic antidepressants, monoamine oxidase inhibitors, and a tetracyclic antidepressant, mirtazapine, are associated with the most substantial weight increases, while selective serotonin reuptake inhibitors typically induce weight gain after prolonged use. Antidepressant agents provide varying risk of associated weight gain, including significant within-class differences. Some agents, such as mirtazapine, show significant levels of weight gain, while others, such as bupropion, demonstrate weight-loss effects.
Meta-analysis by Alonso-Pedrero et al. of 27 cohort studies with over 450,000 individuals found that the most significant weight gain was associated with TCAs, mirtazapine, and certain SSRIs. This study concluded that many individuals treated with antidepressants were at increased risk of gaining 5% of their baseline body weight.
A new study provides some context by suggesting how much weight, on average, people taking one of eight commonly used antidepressants might expect to gain. Published July 2024 in Annals of Internal Medicine, the new study drew on data from more than 183,000 people between ages 20 and 80. Their average age was 48, and 65% were women. The researchers analyzed participants' electronic health records and body mass index. Citalopram, fluoxetine, and venlafaxine didn't confer lower or higher odds of weight gain than Zoloft, the study found. And only bupropion was associated with a small amount of weight loss - 0.25-pounds - at six months. It's crucial to keep in mind that the study points out average weight gain. Many people taking antidepressants won't gain any weight and others could gain more.
Bupropion: An Exception
Bupropion, a norepinephrine-dopamine reuptake inhibitor, is the only commonly prescribed antidepressant consistently associated with weight loss or neutrality. Bupropion is an NDRI, or norepinephrine and dopamine reuptake inhibitor. This class of medications works to increase levels of the mood-altering chemicals norepinephrine and dopamine, which can help regulate hunger cravings.
Strategies for Mitigation
Mitigation strategies include switching medications, adding agents like metformin or GLP-1 receptor agonists, and incorporating behavioral interventions. Weight loss with any medication is most effective when combined with lifestyle changes like eating a healthier diet and exercising more.
If weight gain is a particular concern for you, you may also wish to consider nondrug treatments for depression. Repetitive transcranial magnetic stimulation (rTMS), a brain stimulation therapy that is noninvasive. "We know that certain kinds of talk therapies, especially cognitive behavioral therapy, can be very effective for treating depression and anxiety disorders,"
GLP-1 Receptor Agonists
Researchers noted that overall, about 2 percent of people given antidepressants over the one year period in 2022 were prescribed GLP-1RAs over the ten year period. And people who took GLP-1RAs were also more likely to need antidepressants compared to those who didn’t take them. According to the researchers, the medications themselves might influence mood directly. The researchers also suspect that there could be biological mechanisms that link GLP-1RA use to depression. It’s possible that the drugs have an influence on brain chemistry that alters mood, although the exact pathways remain unclear. “We also found that the association with GLP-1 RAs was not specific to a particular class of antidepressant, although it was particularly strong for duloxetine. Healthcare providers should carefully monitor the mental health of patients treated with GLP-1RAs.
When is Weight Loss a Concern?
Talk with your healthcare provider if you experience a sudden or drastic change in weight, like dropping 5-plus pounds within a week. “Unexplained weight loss may signal an underlying health issue that needs to be assessed,”
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