No 52 - The History and Summary of Anti-Depressants
tldr:
This article is a a very brief history of depression and summary of the condition. I have also produced a timeline of the treatments and summarised how they work and how effective they are. There is a list of useful papers and resources at the end.
If you are revising for the exam, and just want the quick answer then most antidepressants are about 50% effective for severe depression after 8 weeks. Thats about all we can really say…
Hello and welcome to another deep dive into medical pharmacology, pathophysiology and history. This article is going to quickly list all of the facts that you should ever need to know about the history and pharmacological treatment of depression, unless you want to be a pharmacologist or psychiatrist.
If you like these types of articles then have a look at the following:
What I'd like to know about the history of medications
A history of diabetes mangement
If you would like a book that covers all of the basic facts about most common medications, then I can’t not recommend this highly enough: The Top 100 Drugs: Clinical Pharmacology and Practical Prescribing
A very brief introduction to the medications used in psychiatry and general practice in the UK. Psychiatrists prescribe psychotropic drugs, such:
Antipychotics - typical and atypical
Antidepressants - TCA, MAOIs, SSRIs, SNRIs,
Mood stabilisers - Lithium, Carbamazepine, Valproate,
Anxiolytics - Benzos, Buspirone,
Hypnotics - Benzos, Z-drugs,
The following paper is excellent and if you would like more detail than I summarise in this article then please have a read of this:
Pereira, V., & Hiroaki-Sato, V. (2018). A brief history of antidepressant drug development: From tricyclics to beyond ketamine. Acta Neuropsychiatrica, 30(6), 307-322. doi:10.1017/neu.2017.39 https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/brief-history-of-antidepressant-drug-development-from-tricyclics-to-beyond-ketamine/B5C9D55C6299BC41B237187DB609DB68
A very interesting way to look at the medications used at present is to compare what is “common practice” in the UK, with UK guidelines and then compare that to the WHO essential list. The essential list is below and its recommendations are very old fashioned compared to what we now do in the UK. Just an interesting observation about medical practice differences around the world.
World Health Organization CGF. Improving access and appropriate use of medicines for mental disorders. Geneva: World Health Organization, 2017; Available at http://apps.who.int/iris/bitstream/10665/254794/1/9789241511421-eng.pdf. Accessed April 10, 2017
The Psychotropic medicines on the WHO Model List of Essential Medicines – Box 1
The WHO has decided the following have the best evidence for effectiveness and safety! And are the cheapest per QALY.
Psychotic disorders – Chlorpromazine, fluphenazine, haloperidol, risperidone, clozapine
Depression – amitriptyline, fluoxetine
Bipolar – carbamazepine, lithium, sodium valproate,
Anxiety – diazepam
OCD – clomipramine
Addiction – nicotine replacement therapy, buprenorphine, methadone,
1. When was the condition described and by who?
2000 BCE – Mesopotamia – written accounts of depressive symptoms due to spiritual causes or demonic possession
Hippocrates described melancholia
During the dark ages, it was again thought to be due to demonic possession and treated with exorcism, burning, drowning, flogging and starvation.
1621 – Robert Burton wrote “the Anatomy of Melancholy” and suggested the social and psychological cause of depression – diet, exercise, music, travel and herbs are suggested as treatments.
1895 – Emil Kraepelin differentiated Bipolar from schizophrenia (I am paraphrasing in modern language)
1917 – Sigmund Freud wrote about mourning and melancholia
1960s – Aaron Beck proposed the cognitive theory of depression
1970s – Major Depressive Disorder was first defined and became part of DSM III in 1980.
2. What is the natural course?
1/5 people will suffer from depression in their lifetime
>300 million people world wide
Major depression can lead to suicide
Median onset is age 20 and 2xF: 1xM
3. What are the signs and symptoms?
DSM V = 5 symptoms every day for 2 weeks = Major Depressive Disorder (MDD)
Low mood (obviously) + change in appetite/weight + sleep changes + psychomotor activity + loss of energy/fatigue + feelings of worthlessness + reduced concentration + suicidal ideation or deliberate self harm (SI + DSH)
Must impair occupational or social functioning
4. What is the pathophysiology of the condition?
Major Depression = biological model = low levels of monoamine neurotransmitters = monoaminergic system = serotonin (5-HT), norepinephrine (NA) and dopamine (DA)
Medications work by allowing neurotransmitters to accumulate near receptors for longer and increase the strength of their signalling. This seems to elevate the mood.
Unhappiness = expectations > reality
It takes 2-4 weeks for the effects of most antidepressants to be noticed. Despite rapid rises in monoamines within the synapses.
A 6 month course = normal = to significantly improve + stabilise mood + prevent relapse.
Ketamine blocks the effects of the glutamatergic mediator glutamate on the NMDA receptor (NMDAR) by physically blocking the receptor channel but also affects opioid receptors and blocks the reuptake of monoamines
5. What is the natural mortality and morbidity rate?
a. 1/3 recover within a year according to Hohman (1937), when no treatment was available.
b. ¼ recover within 2 years
c. 15% remain chronically depressed in the 1930s, these days its closer to 10% will relapse.
d. Suicide is the leading cause of death for young men <50 years old in the UK
6. Are you likely to die from this or something else?
Suicide is the 14th most common cause of death ranked by the World Health Organization
Approximately 2% of patients treated for MDD in an outpatient setting will die from suicide
Among those admitted for inpatient treatment of MDD – 4% complete suicide
Previous suicidal attempts increases lifetime risk to 6%
Men with MDD have a 7% risk, compared to women with a 1% risk of completing suicide
60% of those who have committed suicide were diagnosed with a mood disorder
90% of those who commit suicide have a mental health diagnosis.
Suicide rates for those with depression are 2-15%
Suicide rates for those with bipolar are 3-20%
Suicide rates for those with schizophrenia are 6-15%
https://www.psychiatrictimes.com/view/characteristics-completed-suicides
Patients with more severe self rated symptoms and less social support are more likely to report suicidal ideation https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-020-02758-y
7. What was the first treatment and was it effective?
1950s - Iproniazid was developed as an anti-TB drug but caused extreme euphoria and hyperactivity in patients.
1952 - It was found to inhibit the monoamine oxidase (MAO) enzyme in the liver and brain
Other drugs were found to block MAO and were called MAO inhibitors (MAOi). These all caused euphoria.
1959 – Imipramine was found to reduce the reuptake of noradrenaline (NA)
9. The Timeline - When was each medication discovered and by whom?
240 BCE - The ancients Greeks proposed – massage, diet, music, baths, gymnastics and poppy extract (opioids)
Asylums and rest
1895 - Emil Kraepelin - tinctura opii
1917 - Psychotherapy and psychoanalysis – talking therapies
Early 20th century – opioids and amphetamines were commonly used for low mood
1930s – Catatonia could be induced and relieved by some drugs
1937 - Ernest Forneau and Daniel Bovet – the first anti-histamine
1940s – Charpentier, Bovet, Halpern and Ducrot would on longer lasting antihistamines = Promethazine = sedative and antipsychotic
Chlorpromazine = 1st antipsychotic
1940s – Electroconvulsive therapy (ECT) developed by the psychiatrist Von Meduna in Hungary.
1950s – Monoamine oxidase inhibitors (MAOI) – isocarboxazid, phenelzine, tranylcypromine,
1952 – Iproniazid = MAOI = Selikoff and Robitzek
1953 – Salzer and Lurie first coin the term “anti-depressant” referring to a side effect of Isoniazid (a TB antibiotic).
1957 – Imipramine = TCA = first reported to have anti-depressant success by Kuhn and first used in practice in Switzerland.
1950s – Tricyclic antidepressants (TCAs) – imipramine (1957), amitriptyline (1961), desipramine (1964), nortriptyline (1963) trimipramine, protriptyline (1966), iprindole (1967), dothiepin and doxepin (1969)
1964 – Ketamine (a dissociative anaesthetic) was used in human trials for the first time-Parke, Davis, Domino . The experiment was done on prisoners in Jackson Prison, Michigan, USA.
1965 – The catecholamine hypothesis of depression = low adrenaline and NA = Schildkraut, Bunney and Davis
1969 = The Serotonergic model of depression =Lapin and Oxenkrug and Coppen
1982 = the 1st SSRI = Zimelidine was marketed in Sweden but was withdrawn over concerns about Guillain-Barré Syndrome
1980s – Selective serotonin reuptake inhibitors (SSRIs) – fewer side effects than MAOI and TCA – Fluoxetine (Prozac, 1987, Eli Lily), Citalopram (1989, Lundbeck, Denmark) paroxetine (1991, Sweden, Novo Nordisk), sertraline (Zoloft, 1990, UK Pfizer).
The SSRI class of drugs was the first to be rationally researched based on the physiology of disease.
1989 – Bupropion (atypical antidepressant, dopamine-noradrenaline reuptake inhibitor)
1993 - Selective Serotonin and Noradrenaline reuptake inhibitor (SNRI) – Venlafaxine (Effexor). Duloxetine (2004, Cymbalta), Desvenlafaxine (2008), Milnacipran (2009), Levomilnacipran (2013). SNRI are like more limited (cleaner) TCAs in their neurotransmitter effects.
Nefazodone – atypical antidepressant (selective serotonin-5HT2A receptor blocker, a weak 5-HT reuptake inhibitor) (can cause liver failure)
reboxetine (a selective noradrenaline reuptake inhibitor)
1994 - Mirtazapine (α2-adrenoreceptor blocker)
2000 - Ketamine – Berman et al = shown to relieve depression quickly and to have lasting effects
2019 – esketamine nasal spray approved by the FDA
There are now 8 classes of antidepressants
10. What are common side effects?
Changes in sleep and appetite, nausea and vomiting, tremors, headaches, loss of libido, anxiety and irritability, and increased suicidal ideation (SI) during the first month.
Rare SE include – liver failure, cerebral and cardiac toxicity,
Bupropion – dry mouth, nausea, insomnia
TCA specific – dry mouth, blurred vision, constipation, dizziness and urinary retention (all muscarinic side effects from the histamine blockade)
SSRI rare SE = tics, spasms, agitation and parkinsonism, serotonin syndrome, hyponatraemia, withdrawal symptoms
Toxic in overdose (OD) - TCA, MAOI
Drug interactions with MAOI = tyramine = hypertension and headache
11. What are the benefits of each class of drug?
MAOI – antidepressant
TCA – antidepressant
SSRI – antidepressant, less SE
SNRI – antidepressant, less SE
Buproprion – antidepressant with less effect on libido
Mirtazapine – antidepressant with less effect on libido and causes drowsiness
12. What is the current management?
Anxiety, eating disorders, panic disorder, OCD, borderline personality disorder and depression can all be treated with SSRI as first line and CBT
13. What is the risk reduction?
In mild to moderate depression = medication has no improvement over placebo
34-46% of patients do not improve with any medication (treatment resistant depression)
Roughly 50% reduction in depressive symptoms = good for severe depression but less effective for milder depression. This is similar for all classes of antidepressants versus placebo over an 8 week period. (Cipriani et al 2018)
Approx 30% will recover and will not relapse
14. What is the NNT for each medication?
TCA NNT = 9 (range 7-16), NNH (harm) = 4-30
SSRI NNT = 7 (range 7-8), NNH = 20 – 90
Arroll B, Elley CR, Fishman T, Goodyear-Smith FA, Kenealy T, Blashki G, Kerse N, Macgillivray S. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007954. doi: 10.1002/14651858.CD007954. PMID: 19588448.
NNT = 4 (Leucht et al 2012, Sim et al 2015) – reduced relapses, recurrences and symptoms of depression if SSRI is given long term
Paediatric depression NNT = 9, NNH (additional suicide) = 64
https://www.ncbi.nlm.nih.gov/books/NBK79954/ -SNRI remission rate was 48% and SSRI was 42% but SNRI produces more intolerable SEs.
6x ketamine infusions over 12 days has antidepressant effects that last 19 days. Studies are looking into dosing regimes. ? weekly dosing looks effective.
15. What are the major studies in this field?
1937 - Hohman, LB. A review of one hundred and forty-four cases of affective disorders – after seven years. Am J Psychiatry 1937;94:303–308.
1965 - Domino, EF. Taming the ketamine tiger. 1965. Anesthesiology 2010;113:678–684.
2000 - Berman, RM, Cappiello, A, Anand, A et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351–354.
2009 - Arroll B, Elley CR, Fishman T, Goodyear-Smith FA, Kenealy T, Blashki G, Kerse N, Macgillivray S. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007954. doi: 10.1002/14651858.CD007954. PMID: 19588448.
2015 - Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015 Feb;23(1):1-21. doi: 10.1037/a0038550. PMID: 25643025; PMCID: PMC4428540.
2017 - World Health Organization CGF. Improving access and appropriate use of medicines for mental disorders. Geneva: World Health Organization, 2017; Available at http://apps.who.int/iris/bitstream/10665/254794/1/9789241511421-eng.pdf. Accessed April 10, 2017
2019 – RCPsych Position Statement on Antidepressants https://www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/position-statements/ps04_19---antidepressants-and-depression.pdf?sfvrsn=ddea9473_5
https://link.springer.com/chapter/10.1007/978-81-322-2803-5_26
https://www.verywellmind.com/who-discovered-depression-1066770
Roose SP, Rutherford BR, Wall MM, Thase ME. Practising evidence-based medicine in an era of high placebo response: number needed to treat reconsidered. Br J Psychiatry. 2016 May;208(5):416-20. doi: 10.1192/bjp.bp.115.163261. PMID: 27143006; PMCID: PMC4853640.