A short history of serotonin
A neurotransmitter, serotonin is known for the role it plays in feelings of well-being and happiness.
The serendipitous discovery of clinically useful antidepressant medication occurred about 60 years ago.
So, what are monoamines?
Monoamines are essentially chemicals in your brain, for example serotonin, dopamine and noradrenalin. These are the transmitters most implicated in psychiatric disorders from depression to bipolar and to schizophrenia. Neurons communicate with each other by releasing monoamines into clefts between them called synapses. The signaling neuron releases an array of monoamines into the cleft and these lock into receptors on the receiving neuron. The temporal lobe, and the orchestrations of its perceptual and emotional memory function, is also heavily influenced by monoamine neurotransmitter systems such as noradrenalin, dopamine and especially serotonin which modulate the circuits to enhance and diminish sensory input. Dopamine is the key neurotransmitter that flips the switch when you are lying on your couch watching the game and decide you want to go get a beer. The impetus to initiate a behavior considered by the prefrontal cortex is largely under the energetic control of Dopamine.
In 1967 a postmortem study revealed decreased concentrations of serotonin in depressive suicides. As a result, a pharmacological company began developing chemicals that would selectively inhibit the reuptake of serotonin thereby increasing the concentration of serotonin at the synaptic junction. SSRI’s (Selective serotonin reuptake inhibitors such as Prozac and Zoloft) prevents the reuptake of serotonin into the signaling neuron and allows it to continue its job in the cleft / synapse at an increased concentration. Decades later, a range of antidepressant drugs have been developed that, with few exceptions, enhance monoamine concentrations.
What is depression?
Simply put, depression is associated with the tendency to perceive social cues as more negative; to preferentially attend to aversive information. Differentiating patients with some depressive symptoms from patients with a diagnosed depressive disorder is important.
Stephen Fry: “If you know someone who’s depressed, please resolve to never ask why. Depression isn’t a straightforward response to a bad situation; depression just is, like the weather.’’
The DSM 5 is the diagnostic and statistical Manual of Mental Disorders classifying all disorders of the mind according to the latest criteria set down by the American Psychiatric Association. The DSM outlines a standard of diagnosis that professionals are expected to follow.
An episode of Major Depression is characterized by 5 or more symptoms for two weeks or more. The DSM really nails it down, therefore freeing us from obfuscating doubt.
Symptoms include:
The illness typically emerges during the second decade of life. The mean age of onset is 27 years.
There are various diagnostic checker tools to help if the above criteria are difficult to apply. A diagnostic tool developed by Wits can be useful at www.mddsa.co.za.
Reversal of negative bias with antidepressant drugs
So, at a neural level deep within the brain circuits depressed individuals have an increased response to negative versus positive stimuli. Antidepressant treatment reverses this pattern of neural response. In other words, antidepressants will enhance your response to happy faces and reverse your aversiveness to negative bias. These effects occur very early, before changes in mood, but are related to later clinical change.
“A mark in every face I meet,
Marks of weakness, marks of woe,”
Writes William Blake an 18th century English poet.
Such a negative bias today has been proven in studies to be changed within 3 hours of administration of a single dose of an antidepressant. These early changes in emotional biases probably play a critical role in therapeutic efficacy.
Do these pills work for everyone?
The simple answer is no.
Patients with treatment resistant depression (TRD) might have highly entrenched long standing negative affective biases that are resistant to change. They may also be in a highly adverse social environment that cannot support an improvement in mood despite the changing or adaptation of the negative affective bias by the meds.
Since the generation of Prozac ( first launched to market in January 1988), treatment of Major Depressive Disorder, a common disorder with high incidence and recurrence is seeing new guideline overhauls and newer treatment options.
Treatment
Prior treatment options were less patient choice centered. The 2020 update of the Royal Australian and New Zealand College of Psychiatrists has an updated framework based around 3 approaches:
1. Actions with more emphasis on lifestyle modification (especially aerobic exercise).
2. Potential alternative treatments. Alternatives including rTMS (repetitive transcranial magnetic stimulation), and esketamine are also novel treatments to consider when choice treatments are not effective. I had not heard of rTMS until one of my patients got a quote and for a 5-day treatment plan it was close to R40 000. This treatment involved up to 10 treatments – one per hour each day. rTMS is a relatively new means of stimulation but is not as effective as ECT.
Repetitive transcranial magnetic stimulation (rTMS)
3. Pharmacological choices including the patients’ preferences (e.g., less sexual dysfunction for Bupropion, Agomelatine, Mirtazapine) and less sedation for fluoxetine, Vortioxetine and Escitalopram etc.
Currently guidelines recommend SSRI’s as first line (selective serotonin re-uptake inhibitors), for major depression.
Rapid acting agents for the treatment of depression
A single dose of ketamine, an NMDA antagonist, produces rapid antidepressant action within hours and leads to a rapid resolution of suicidal ideation. Ketamine was able to abolish memory for negative associations for which stimuli had been paired with.
Conventional antidepressants like SSRI’s change only positive processing of incoming information but ketamine may be able to change or reduce memories of already encoded memories.
Work using a rodent model of negative affective bias suggests that while conventional antidepressants improve the acquisition of a positive bias, they do not change the retrieval of previously obtained negative memory associations. By contrast, ketamine was able to abolish memory for negative associations that stimuli have been paired to. Ketamine may reduce memories of the ‘already encoded’, thus improving the mood faster.
The antidepressant effect persists for several days but then wanes.
Repeated infusions achieved superior antidepressant outcomes as compared to a single infusion. Ketamine infusion can reverse synaptic defects caused by chronic exposure to stress. Future studies are needed to elucidate neural circuits involved in treatment response to ketamine.
Medication strategies
The first approach is to actually START the meds.
If there is an inadequate response then INCREASE the DOSE,
If no response to increased dose, then AUGMENT the antidepressant with an antipsychotic medication or LITHIUM. (i.e., add another drug to improve the working of the first).
If the above approaches have not worked, then switching to another medication is next. Some may opt for medication type in the same class or some for a different antidepressant class e.g., if you are on Prozac and SSRI then your doctor can consider changing to Mirtazapine for example which is a tetracyclic antidepressant
ECT
ECT was first developed in the late 1930’s and it is useful for psychotic symptoms that are present in depression and for the initial treatment where severe psychomotor changes are present, for example not eating or cleaning oneself. It is an effective and safe treatment where patients have not responded to an antidepressant.
Electroconvulsive Therapy (ECT)
Lifestyle modification
Poor sleep patterns and lack of exercise can play a role in the onset and maintenance of depression. Patients can be directed to good quality information about sleep.eg: www.sleepfoundation.org/articles/sleep-hygiene
Regular exercise is associated with significant antidepressant effects while being good for all aspects of health.
Psychological treatments
Psychological treatments include CBT (cognitive behavioral therapy) which are non-pharma treatments that identify negative thinking and help clients learn more beneficial ways of thinking and behaving. Some wise words from Yoda on a galaxy far away: “You must unlearn what you have learned”
Psychological therapies develop resilience and assist with relapse prevention and can avoid medication side effects.
The South African Depression and Anxiety group lists local support groups, hotline numbers and digital resources for online therapies. (www.sadag.co.za)
Withdrawal symptoms
Antidepressant withdrawal symptoms are notoriously underestimated with up to 56 % of patients experiencing withdrawal after stopping their medication. Common withdrawal symptoms include similar ones to the symptoms that necessitated their use in the first place e.g., low mood, irritability, anxiety and tearfulness as well as many others that mimic anxiety. The risk of withdrawal is higher with longer duration of use and higher doses and can be counteracted with gradual withdrawal of the antidepressant by the doctor.
Conclusion
Human beings are genetically variable, and the high dimensionality of the genome brings all combinations of strengths and weaknesses to manifest in the species. The good news is that real nurture and love can overcome genes dealt with at birth by nature. By being cognizant of the role of nurturing our offspring we can help prevent at least one leg of what could turn out to be a mental disorder later. Adapting to the fourth industrial revolution and navigating screen free time among the hedonistic pursuits of youth and beyond to the place of work, there has never been such a potential for an explosion of mental health crises. Preventing them to whatever extent we can with regular exercise, mindfulness and online CBT tools is imperative. (cimhs.com is a free interactive therapy program for depression that you can complete on your own). A new and exciting framework is available to manage and treat depression. From psychological treatments to pharmacological options with rapidly developing new treatments in the field of psychedelics, there is a transformative change in the way we treat depression and it’s not all in a capsule.
By Dr Wendy Dicks
References:
Managing Depression
Using a clinical practice guideline approach
Modern Medicine Volume 48 Number 2 Issue 2. 2023
Authors of the article:
Philip Boyce MD FRANZCP Emeritus Professor of Psychiatry
Erica Bell BSc (Hons)
Gin S. Malhi MBChB
The Psychopath Inside (Novel)
By James Fallon research neuroscientist at the University of California, Irvine.
Effect of acute antidepressant administration on negative affective bias in depressed patients (Article)
Published in the American Journal of Psychiatry 2009; 166:1178-1184 by Catherine j. Harmer, D.Phil. et al
A translational perspective on the anti-hedonic effect of ketamine and its neural underpinnings
Article published in Molecular Psychiatry (2022) 27:81-87
