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Since all patient experiences are unique, “differences” are either more objective than experiential (like chemical structure) or more statistical than determinant (like clinical trial results).So, any “major differences” tend to be more about how we choose to organize our labels and how we decide to run and interpret our research. In fact, that collection of biases is what defines “antidepressants” as a class of drugs in the first place, in addition to subsequently giving rise to the individual antidepressant classes most often given letter soup designations (eg SNRIs, TCAs, MAOIs…).I will discuss some of the organizational, institutional, and cultural differences below. This is not meant to be comprehensive or absolute, but hopefully addresses some of your curiosity. I am not a doctor, pharmacist, or other healthcare professional, but these facts are easily accessed through medical journals and other academic sources.Binding Profile / General Actions - What’s it do?Each antidepressant has a different binding profile, but each class of antidepressants is generally created around the chemical structure of the drug and/or its most prominent binding preferences (with “prominent” being arbitrary defined). Not all drugs fit neatly within any particular class, and all drugs marketed as antidepressants act globally.“Binding” is a bit simplified, as well, because there is action (agonism, antagonism, etc) and also non-binding effects (like you would see in MAOIs, for example). More broadly speaking, you could just say “what they do” loosely contributes to how classes are grouped, and what traits an individual antidepressant is considered to exhibit. Convenience, application, marketing, and other determining influences contribute to drug conceptualizations and class designations, and to how “what they do” is interpreted and contextualized in communications.The actions and influences of all antidepressants are so similar that the potential side effects are still almost universal across all drugs and classes. It is rare that some kinds of drugs have risks that are not present in other classes, and such distinctions usually fall back to mechanisms—like MAOIs and particular dietary and drug interaction risks versus the complications of using drugs focusing on altering reuptake (which is almost all the rest of the commonly prescribed antidepressants, like SSRIs, SNRIs, TCAs, NDRIs, etc). However, the differences in binding profiles and other elements (like metabolic profiles) creates different statistical likelihoods of particular side effects. Together, these factors sometimes create the generalization that certain drugs or classes may have different average experiences from one another.Cost - How much do I pay?…And why?Newly patented antidepressants oftentimes have no direct generic competition, due to how intellectual property philosophies and other related legislation works. This can mean certain drugs are way more expensive, even if they are in the same class as drugs which are much cheaper due to a loss of patent protection. In cases where a new drug is considered novel (not otherwise classifiable in previous paradigms) or a class designation is exclusively containing on-patent drugs, cost can be a substantial differentiating factor between entire classes (like how it once was with SNRIs) rather than single drugs.Insurance companies will not generally cover all antidepressants equally, or even all antidepressants within a specific class equally in some cases. Which drugs or classes are preferred by their formulary is about their bottom line rather than what is efficacious, appropriate, or most fitting for specific patients, though sometimes there can be convergent interests served. This is not strictly related to the previous category of “what they do”, either, so politicking and non-medical practicalities can shape the ‘major differences’ between commonly prescribed antidepressants.Approval / Legality - Is this sanctioned? Is it criminal?Drug approval varies from one country to the next, and from one time period to another. Though prescription drugs are often ruled on through individual evaluations of perceived merit, sometimes entire classes of drugs end up being unapproved or banned in some times or places. This can impact prescribing practices, patient health, drug importing/exporting, common recreational uses, and other logistical and experiential aspects of antidepressant drugs and drug classes.Some drugs are explicitly approved for what may otherwise be related or entirely off-label uses. Off-label prescribing is far more common than approval for expanded usage, and the reasons for companies to pursue approval for additional uses are probably multifactoral. Unapproved prescribing is ubiquitous, and does not always leave a paper trail for researchers to study because insurance companies may require particular diagnoses be cited.Approval is not the only side of this, as legality can be a concern as well—some drugs are not only unapproved for prescribing and dispensing as pharmaceuticals, but also considered illegal to grow, manufacture, possess, sell, or transport. There are many possible examples of drugs used as antidepressants which can be illegal or highly restricted in places where psychiatry is quite popular, like cannabis, psilocybin, DMT, LSD, MDMA, and so on.Prescribing Trends - What are doctors and patients doing?Though all antidepressants are reported as being equally efficacious (or unefficacious, depending on your perspective) for what we think of as primary concerns of psychiatric use, like major depressive disorder or even anxiety disorders in some cases, prescribing trends relate more to factors which reach far beyond the efficacy reported in clinical trials. There are sometimes drug-based and class-based perceptions and lore, as well as other conceptualizations of antidepressant drugs and classes which are essentially a part of psychiatric culture—the ideologies and trends of particular times and places in psychiatric practice, oftentimes created through practical experience and personal bias rather than dissemination of media or the formalizing of medical dogma.As with all other categories, prescribing trends are interdependently associated with things like approval, cost, and binding profiles. Given this complex dynamic, no one element is independent or uniquely hierarchically determinant rather than being interdeterminant. That patients respond unpredictable and individualistically to each drug, dose, treatment context, and treatment duration means the complexity involved in the wider dynamic has implications for how antidepressants are used in each specific patient. We can sometimes group patients in similar ways to drugs themselves by examining prescribing trends and following the influences back out to the interdependent relationships and the way those relationships interact with patient-side concerns and experiences (like income level, access to specialist prescribers, toleration of off-label uses, personal familiarity with a product, etc).If you want a breakdown of where each antidepressant and drug class fits into these categories, you may be better off reading a psychopharmaceutical textbook or checking PubMed for free full articles exploring the perceptions, uses, and research behind each respective drug. Even sources like online textbooks, Wikipedia, and the prescribing information for each drug through the FDA website or drug company websites can help you come to a fuller understanding of the issue.If you are really desperate for this information to be added to my post, I can amend it later should you request I do so, but you are largely asking about things that are more subjective than universally believed. Chemical structures are concrete and we pretty much have consensus about that, but asking about things like efficacy gets political and asking about things like cost gets highly specific to particular regions and eras.That is why I tried to give an outline of how differences are formed rather than where each of the many dozens of drugs fit into the various categories—especially since “class” is such a loose organizational system that a lot of overlap or ‘weird’ exceptions crop up. For a bit more information, you can read other posts of mine on the topic, like this one here: Mark Dunn's answer to Are there medications for depression?You can also check out other Quora discussions (or off-site discussions) where patients, professionals, and other individuals share their own take on the differences you are asking about, such as:What are the major and clear differences in the situations when the following antidepressants are prescribed; the SSRIs, the NDRI and SNRI?For severe depression, how do psychiatrists know when to prescribe SSRIs and when to prescribe SNRIs?