Antidepressants aren’t happy pills.

“Isn’t that the one you hear middle-aged women talk about on Desperate Housewives?” My patient wasn’t wrong. Though it was the first in its class of medications, Prozac remains one of the most widely prescribed antidepressants today and for this reason makes its way into movies and television, frequently as the brunt of a joke.

I’ll set the television scene. A wealthy, middle-aged woman, whose husband travels frequently in his ill-defined role as a financier, sits with a group of similarly dressed friends sipping chilled white wine at 9 in the morning. Someone makes a comment about how stressed they’ve been since their second gardener quit last week, leading one in the group to quip, “Did you take your Prozac this morning?” In fact, she hadn’t, so out comes the small glittering pill case. “I’ll take an extra,” she says, using the wine to wash down a double dose (note: the use of alcohol and antidepressants together is not recommended). Sighing with relief, they return to gossip about the new neighbor who may or may not have gotten her fortune through marriage to a series of older gentlemen who died under mysterious circumstances.

No wonder my patient doesn’t want to be associated with the medicine. Nevermind that everything about the above picture is incorrect. Prozac, and other antidepressants, aren’t “Happy Pills”; they don’t intrinsically produce happiness in those who aren’t depressed. They don’t even produce “happiness” in those who are depressed. In addition, they don’t work as quickly as described above, nor could they resolve the problems our fictional patient may be having in her marriage, her household, or the neighborhood.

So if antidepressants aren’t happy pills, what do they do and how do they work?

Though many of the mechanisms of antidepressants are little understood, we do know potential pathways through which they may exert their effects.

First, we need to understand that not all antidepressants are the same. Within this broad classification are several subclasses including SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), Atypical antidepressants, TCAs (tricyclic antidepressants), and MAOIs (monoamine oxidase inhibitors).

To speak broadly, the SSRIs and SNRIs prevent reuptake of neurotransmitters (serotonin in the case of SSRIs and serotonin and norepinephrine in the case of SNRIs), which allows them more time in the space between two neurons (called the synaptic cleft). Allowing more time in the cleft between two neurons increases the chances that a signal (called an action potential) is propagated from one neuron to another. This is also why antidepressants are often described as “initially activating”. This is because at initiation of an antidepressant we see increases in cell signaling. Many patients will experience an initial increase in anxious or negative thinking for this reason. It’s important that practitioners explain this to patients so they don’t think the medication is making their condition worse.

Complicating the picture for patients is the number of these medications produced. Though in large studies no single antidepressant has emerged as superior, this doesn’t mean they are all the same. Though we don’t understand exactly why (though emerging genetic research is giving clues), patients may not respond to one medication, but dramatically respond to another medication in the same class. In addition to differences in individual patient responses, these medications also differ in their side effect profile. The correct selection of a medication is dependent in part on which side effects a patient would most like to avoid, or more favorably, if we can use a side effect to our advantage (i.e. improved sleep in someone who can’t sleep, more energy in someone who lacks energy, etc.).

Other antidepressants, often termed atypical antidepressants, work in unique ways; they may impact serotonin or norepinephrine but also can include dopamine which is important in motivation, appetite regulation, decision-making, among other important functions. These medications are selected based on patient presentation and side effect profile. For example, an agent that is more sedating would not be a first-line agent for someone dealing with increased daytime fatigue. Nor would an agent that produces more wakefulness/energy be ideal for someone experiencing anxiety or agitation. There is no one-size-fits-all approach to mental health care. We should be wary of any medication recommended before sufficient time has been spent to listen to a patient's symptoms and daily experience.

MAOIs and TCAs are some of the first antidepressants created and have been utilized less and less with the invention of SSRIs and SNRIs though they may be helpful in patients who have cases of resistant depression.

In addition to the effect on neurotransmitters, new theories about the anti-inflammatory impact of antidepressants or their impact on our stress hormone system (HPA axis) have emerged to explain their potential mechanism of action.

Emerging research has targeted the neurotransmitter glutamate as well as NMDA receptors and seem to produce more rapid results than other antidepressants. These are now termed RAADs (Rapid Acting Antidepressants). Ketamine infusions (a dissociative anesthetic used in the operating room for decades) are a member of this newer class of medications (for more information about ketamine and concerns Christians may have about its use see here).

As is the case with much of psychiatry, we continue to discover more about how the brain and mind work and how we might find novel targets to help patients experiencing depression or anxiety.

What do we hope these changes in neurotransmitters do for our patients?

As serotonin adjusts in the brain, several notable things happen in thought life. First, thoughts become less “sticky”. Instead of an intrusive or unwanted thought taking up hours of brain space, the thought is more easily labeled as unhelpful and it is brushed aside.

Secondly, as these medications reach therapeutic levels, patients may notice they more readily begin to challenge automatic negative thoughts. The vast majority of thoughts we have in any given day go unnoticed, left in the subconscious. When those who are depressed or anxious begin to take notice of their internal mental track (the things they are telling themselves), most are shocked by what they find. For days, months, even years, these thoughts have gone unchallenged. As patients initiate these medications, they often begin to question thoughts, “Is that true?”, “Is it completely or only partially true?”, “Is it possible the opposite is true?” among others.

Thirdly, we hope to set the stage for heart work to be done. At the Christian Counseling and Education Foundation (CCEF) conference last year (2023), counselor and physician Mike Emlet said in a talk, “Doing heart work while anxiety or depression is present is like trying to do a deep sea diving expedition while hurricane force winds are present on the surface of the sea.” Counselors recognize that doing heart work in these conditions isn’t just difficult, it’s nearly impossible.

So why aren’t antidepressants happy pills?

Antidepressants help set the stage for effective heart and mind work. It is difficult to work through complex interpersonal relational issues, work and home-life stressors, or make major decisions when thoughts won’t stop ruminating, when the whole world seems hopeless or dark, or panic/anxiety bring any effective problem-solving to an abrupt halt.

For the person who feels low, hopeless, or depressed, antidepressants don’t make them “happy”. A better description would be that these medications bring patients back to a “neutral”. By neutral, it’s important to distinguish this from feeling “flat”. Though high doses (or the incorrect fit of an antidepressant) can lead one to feeling flat, this is not the intent of prescribing these medications and would be reasons to adjust the dose, augment the medication, or discontinue altogether to try something else.

These medications take time to work. This is because part of the mechanism of action is a change in thinking (a renewing of the mind), which doesn’t happen overnight. This is part of the reason we believe the combination of medication and therapy is so powerful. Medication prepares the soil, counseling provides the space and direction necessary to cultivate the right thought patterns.

In summary, for the Christian, we hope the use of this class of medications doesn’t just lead to a “happy life” but that we might faithfully pursue the admonition to “not be conformed to this world, but be transformed by the renewal of your mind, that by testing you may discern what is the will of God, what is good and acceptable and perfect” (Romans 12:2, ESV)."

Adam O’Neill, PA-C is a Psychiatric Physician Assistant and owner of Adam O’Neill & Associates, author of The Mind after Eden: Psychiatry in a Post-Fall World, The Patience of Hope: Encouragement for the Sufferer through the life and ministry of George Matheson, and The Mind for His Glory: A Theory of Applied Christian Psychiatry (forthcoming), and serves as executive director for the Faith and Medicine Foundation. He is a member of Capitol Hill Baptist Church in Washington, D.C.