Do you think that depression is associated with or even caused by lowered concentrations or activity of serotonin in the brain? This is the well-known monoamine or “chemical imbalance” theory of depression.

I can still recall watching many a psychiatrist at the hospital where I worked as an intern psychologist draw little pictures of serotonin transporters in the brain for patients, showing that a serotonin-altering antidepressant medication would help serotonin to hang out in the brain longer, therefore having more chance to exert its mood-enhancing effects and balance out depression.

In 2022, a massive review study led by psychiatrist Dr Joanna Moncrieff was published that reviewed the existing published research on this theory of serotonin and depression. Their conclusion officially turned the often-cited explanation for depression as being a problem with serotonin on its head - which has led to mass public discussion and some confusion for those using antidepressant medication for depression.

Where did this idea come from?

Starting in the 1950s with the accidental discovery of a medication that was found to alter serotonin and impact mood, the serotonin hypothesis grew to shape a dominant understanding of depression as being associated with insufficient serotonin and other neurotransmitters (e.g., noradrenaline, dopamine) in the brain. This lent itself to increased prescribing of antidepressant medication with selective serotonin reuptake inhibitors (SSRIs), such as Sertraline, or serotonin/noradrenaline reuptake inhibitors (SNRIs), like Venlafaxine. Prescribing rates of these and other antidepressants have increased over time and between 2008 - 2015 about 1/8 New Zealanders (and 1/6 NZ women) were found to have a prescription. Though designed for the treatment of depression, they are now prescribed for a multitude of mental health experiences - including panic attacks and anxiety (e.g., social anxiety, generalised anxiety, phobias), insomnia, emotional dysregulation, obsessive-compulsive disorder, and post-traumatic stress disorder. They are also prescribed for some non-mental health purposes - like pre-menstrual syndrome, chronic neuropathic pain, or chronic fatigue syndrome.

While some people report finding antidepressant medication extremely helpful, others describe no positive effects and many of these experience unwanted adverse effects. Adverse effects of the medication can include an array of physical health symptoms such as nausea, dry mouth, weight gain, inability to get an erection, low arousal or the inability to climax. There can also be mental health adverse effects including emotional blunting, drowsiness, and even suicidality for some. Adverse effects can range from mild to severe and are often a reason that discontinuation of the medication is desired.

In a recent self-report study, over 50% experienced withdrawal effects when trying to stop depression medication, with nearly half of those people reporting those effects as severe. Withdrawal effects are usually referred to as “discontinuation syndrome” in the literature and this New Zealand-based article describes some personal examples of the severe experiences encountered that render some people entirely unable to function. Symptoms can involve “brain zaps”, insomnia, dizziness, flu-like symptoms, and nausea among other unpleasant things. When these occur for a prolonged period or seem to be getting worse over time, people often return to their medication and report feeling trapped and hopeless about ever being able to be medication-free. The 2022 review actually found some evidence that long-term use of SSRI medication itself may lower the concentration of serotonin and so there may be medication effects that impact mood and the ability to cease SSRIs.

So what does this all mean for those with depression who are using and benefitting from SSRI medication, or who are perhaps experiencing adverse effects and even struggling to withdraw?

• First of all, it does mean that if anyone is still using the low serotonin hypothesis to explain depression they should probably stop.

• Secondly, it doesn’t necessarily mean that SSRIs and other antidepressant medications don’t “work” - but it does mean they are probably having their effects in other ways which we don’t entirely understand.

• If you are using or have used antidepressants and they have been helpful for you then there may be other mechanisms that explain what they are doing to be helpful.

• If you are using antidepressants and have found unwanted adverse effects or debilitating withdrawal reactions you are not alone and you may need professional support to work out a safe and sustainable tapering plan.

Other fascinating research on how SSRIs might operate:

1. Plenty of research by psychologist Irvine Kirsh has explored the role of placebo and found much of the effect could be explained by the incredible power of our minds and beliefs when it comes to our health. Placebo is a legitimate and positive effect we can leverage and simply means that the belief or faith we hold in a certain intervention is a large part of what helps it to work for us. If someone believes the serotonin theory is the cause of their depression (helped along by a health professional explaining that the medication will impact their neurotransmitters to enhance mood) and they take an SSRI then the power of this belief can account for a large component of their response to the medication.

2. Another explanation is that SSRIs may support the growth of new neurons in the hippocampus, a region of the brain that has been found to shrink under stress and in those experiencing depression. This neurogenesis of brain-derived neurotrophic factor (BDNF) is also found to occur using other approaches to health - including certain types and amounts of exercise as well as supplementing the mineral zinc (in fact, some research found that SSRI plus zinc was even more effective than SSRI alone - more about this here).

3. New and interesting research has looked at the potential anti-inflammatory effects of SSRI medication. This aligns more with the modern cytokine theory of depression - that inflammation in the body may cause or drive feelings of low mood, tiredness, lack of motivation and social withdrawal. This leads to the more interesting question - where does the inflammation come from? And is there a relationship between this and the increased rates of depression, anxiety and chronic health problems these days?

Any one model of any type of mental health concern oversimplifies a complex and very human issue - and there are many potential contributing or causal factors to depression including the non-pathologising notion that it can be at times an adaptive response to an unworkable situation - designed to help someone withdraw and make radical life changes.

However, given that placebo, enhancing neurogenesis, and reducing inflammation may all be powerful pathways to enhance mood, this opens the door for other interventions with less potential adverse effects to play a more central role in depression prevention and recovery.

Note: if you are currently using medication for depression and would like to explore stopping please create a tapering plan for this with a registered mental health professional and/or your prescribing doctor. A tapering plan enables you to gradually lower your dose at a pace that works for you to manage any discontinuation symptoms. Never abruptly stop taking medication as you may experience withdrawal symptoms ranging from mild to severe.