Antidepressants are an important class of drugs in modern medicine, providing people with relief from the crippling effects of depression.
Recently, research has suggested that some of these drugs may also provide benefits to people suffering from Parkinson’s disease. But by saying this we are not talking about the depression that can sometimes be associated with this condition.
This new research suggests anti-depressants are actual providing neuroprotective benefits.
In today’s post we will discuss depression and its treatment, outline the recent research, and look at whether antidepressants could be useful for people with Parkinson’s disease.
It is estimated that 30 to 40% of people with Parkinson’s disease will suffer from some form of depression during the course of the condition, with 17% demonstrating major depression and 22% having minor depression (Click here to read more on this).
This is a very important issue for the Parkinson’s community.
Depression in Parkinson’s disease is associated with a variety of poor outcomes not only for the individuals, but also for their families/carers. These outcomes can include greater disability, less ability to care for oneself, faster disease progression, reduced cognitive performance, reduced adherence to treatment, worsening quality of life, and increased mortality. All of which causes higher levels of caregiver distress for those supporting the affected individual (Click here to read more about the impact of depression in early Parkinson’s).
What is depression?
Wikipedia defines depression as a “state of low mood and aversion to activity that can affect a person’s thoughts, behaviour, feelings, and sense of well-being” (Source). It is a common mental state that causes people to experience loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration.
Importantly, depression can vary significantly in severity, from simply causing a sense of melancholy to confining people to their beds.
What causes depression?
Stress, health, and chemistry are the three primary causes of depression.
Traumatic events (such as the loss of a loved one or the diagnosis of a life-altering condition) can significantly affect one’s mood and outlook on the future. Neglecting one’s health or abusing substances (for example excessive drinking of alcohol) can also lead to a worsening in one’s feelings of self worth. In addition, there are also some health conditions that may cause depression-like symptoms (for example, hypothyroidism is known to cause depression in some people). And this relates to changes in the brain’s delicate chemistry which directly affects mood.
Within the brain there are two chemicals that are recognised as affecting depression, these are:
Serotonin – sometimes referred to as the happy neurotransmitter (a chemical messenger between cells), low levels of serotonin in the brain can be caused by sustained stress in animal models, and low serotonin activity is associated with a higher risk of suicide (Click here to read more about this).
Dopamine – the chemical behind motivation. Dopamine encourages people to achieve goals and desires, and issues a surge of reinforcing pleasure once they’ve been accomplished. Low dopamine levels may make people less likely to work toward achieving a goal (Click here to read more about this).
How is depression treated?
Depression is usually treated using a combination of self-help, talking therapies and medicines.
With regards to seeking self help and talking therapies, the following groups can help in the UK
- Samaritans (116 123) operates a 24-hour service available every day of the year. If you prefer to write down how you’re feeling, or if you’re worried about being overheard on the phone, you can email Samaritans at email@example.com.
- Childline (0800 1111) runs a helpline for children and young people in the UK. Calls are free and the number won’t show up on your phone bill.
- PAPYRUS (0800 068 41 41) is a voluntary organisation supporting teenagers and young adults who are feeling suicidal.
- Depression Alliance is a charity for people with depression. It doesn’t have a helpline, but offers a wide range of useful resources and links to other relevant information.
- Students Against Depression is a website for students who are depressed, have a low mood or are having suicidal thoughts.
- Bullying UK is a website for both children and adults affected by bullying.
With regards to the medication, there has been a long history of attempts to treat depression with medication:
The modern history of anti-depressants. Source: Compoundchem
These drugs attempt to treat depression by addressing the chemical imbalance in the brain using drugs that affect the chemicals mentioned above, particularly serotonin.
Selective serotonin re-uptake inhibitors (or SSRIs) are the most widely prescribed type of antidepressants. When the chemical serotonin is released by a cell, it has an effect on the neighbouring cell and is then rapidly re-absorbed by the cell that released it so that it can be recycled and potentially used again. SSIRs function by blocking the re-absorption of released serotonin back into the cell, thus increasing the levels of this ‘happy neurotransmitter’ that are floating around in the brain. Commonly used versions of SSRIs include Fluoxetine (sold under the brand name ‘Prozac’), Citalopram (‘Cipramil’), Paroxetine (‘Seroxat’) and Sertraline (‘Lustral’).
There are also other types of antidepressants, such as:
- Serotonin-noradrenaline re-uptake inhibitors (SNRIs), which block the reabsorption of both serotonin and another chemical called noradrenaline. Common examples of SNRIs include Duloxetine (‘Cymbalta’ and ‘Yentreve’) and Venlafaxine (‘Efexor’).
- Noradrenaline and specific serotonergic antidepressants (NASSAs), which are similar to SNRIs but generally prescribed to people who are unable to take SSRIs. A commonly prescribed NASSA is Mirtazapine (‘Zispin’).
- Tricyclic antidepressants, which are one of the oldest classes of anti-depressant drugs available – we will come back to these very shortly.
Do we know much about depression in Parkinson’s?
The Michael J Fox Foundation have a good page on depression in Parkinson’s (Click here to see it) as well as this interesting video:
The Parkinson’s UK website also has a good page on depression – Click here to see it.
EDITOR’S NOTE: If there are other Parkinson’s support groups around the world that provide information and support for their members regarding depression, please contact me and I can make the information available here.
Do antidepressants work in Parkinson’s?
With regards to the treatment of depression associated with Parkinson’s, the answer is ‘yes’ but there can be major differences between individuals and between different classes of antidepressants.
Selective serotonin re-uptake inhibitors (SSRIs) are the most commonly-prescribed antidepressants in the PD population (Source), but this class of antidepressants has been associated with increased levels of apathy compared to other types of antidepressants (Click here to read more about this).
Tricyclic antidepressants have long been used to treat depression in Parkinson’s:
Title: Anti-depressive treatment in Parkinson’s disease. A controlled trial of the effect of nortriptyline in patients with Parkinson’s disease treated with L-DOPA.
Authors: Andersen J, Aabro E, Gulmann N, Hjelmsted A, Pedersen HE.
Journal: Acta Neurol Scand. 1980 Oct;62(4):210-9.
In this study, 19 people with L-DOPA treated Parkinson’s disease who also suffered depressive symptoms were treated with the Tricyclic antidepressant nortriptyline. They were compared to a placebo treated control group that also had Parkinson’s. The researchers found that nortriptyline had a clinical significant impact on the depressive symptoms, but the Parkinsonian features were unchanged.
And these results have been replicated numerous times (Click here to read more about this), including in a comparison with a selective serotonin re-uptake inhibitor-based antidepressant:
Title: A controlled trial of antidepressants in patients with Parkinson disease and depression.
Authors: Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, Bienfait K, Dicke A.
Journal: Neurology. 2009 Mar 10;72(10):886-92.
PMID: 19092112 (This article is OPEN ACCESS if you would like to read it)
In this NIH-funded, randomized, controlled clinical trial compared a SSRIs antidepressant (Paroxetine) against a tricyclic antidepressant (Nortriptyline) and a placebo in 52 people with Parkinson’s and depression. After 8 weeks of treatment, the researchers no significant differences between the groups with regards to their Parkinson’s related motor features (as defined by the clinician-based Unified Parkinson’s Disease Rating Scale), but they did note that Nortriptyline was significantly better than Paroxetine and placebo at alleviating depression. Taking Nortriptyline also significant improved sleep quality and social functioning compared to placebo.
Thus, tricyclic antidepressants may be better for treating depression than SSRIs for Parkinson’s.
But what are Tricyclic antidepressants?
Tricyclic antidepressants are a class of antidepressant medications that derive their name from their chemical structure: they contain three rings of atoms.
The chemical structure of the tricyclic antidepressant Imipramine. Source: Wikipedia
First discovered in the 1950s, in addition to depression tricyclic antidepressants are used for a variety of conditions, from ADHD to chronic pain. They have been used for just about everything during their time, including reduction of bed-wetting and prevention of migraines.
They are generally very effective, but they’ve largely been replaced by other types of antidepressants (such as SSRIs) which cause fewer side effects.
Yeah, tricyclic antidepressants have a bad reputation here.
Side effects are relatively common with their use, and they can range from dry mouth to blurred vision. They also include lowered gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature (Source:Wikipedia). This is why people with Parkinson’s associated depression will often be treated with SSRIs rather than tricyclic antidepressants – they simply have fewer side effects.
Interesting, so which anti-depressants are providing the neuroprotective benefits you mentioned above?
Uh, the ones with all the side effects: the tricyclic antidepressants.
Let’s have a look at the research.
This is Prof Tim Collier:
He is the director of the Michigan State University Udall Center of Excellence.
A few years ago, Prof Collier and a research scientist in his lab named Katrina Paumier noticed something interesting about the biological mechanisms associated with the actions of tricyclic antidepressant drugs.
Dr Katrina Paumier. Source: Translationalscience.msu
Prof Collier and Dr Paumier noticed that tricyclic antidepressants regulate pathways involved in cell survival (Click here and here to read some OPEN ACCESS examples). This observation suggested to the researchers that tricyclic antidepressants could treat Parkinson’s-associated depression, but may also slow down the progression of the condition.
They decided to test this idea, which gave rise to this research report:
Title: Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson’s disease.
Authors: Paumier KL, Siderowf AD, Auinger P, Oakes D, Madhavan L, Espay AJ, Revilla FJ, Collier TJ; Parkinson Study Group Genetics Epidemiology Working Group.
Journal: Mov Disord. 2012 Jun;27(7):880-7.
In this study, the researchers used a large database compiled from 6 completed clinical trials (ELLDOPA, QE2, TEMPO, PRECEPT, FS1 and FS-TOO – all conducted by the Parkinson’s Study Group and the Neuroprotection Exploratory Trials in Parkinson’s Disease Project (NET-PD)) to examine whether antidepressant treatment could alter the course of Parkinson’s progression. This shifting of the disease course was determined by the amount of time that passed before initiating dopamine-based therapies in people recently diagnosed with Parkinson’s.
A total of 2064 subjects were included in this analysis, of which 451 were on an antidepressant at some time during the study. What the investigators found in through their analysis was that the time to dopaminergic therapy was shorter for those with baseline depression compared to those without depression, suggesting that the presence of mild depression in early Parkinson’s is associated with needing dopamine therapy earlier. And this finding applied to those individuals who were also taking an antidepressant.
But, when the researcher looked at the different classes of antidepressants being taken, they noticed something interesting: the average time to needing dopamine therapy was longer for those on Amitriptyline (compared to those subjects not taking antidepressants).
Amitriptyline is a tricyclic antidepressant.
Individuals taking tricyclics antidepressants (Amitriptyline in particular) had a lower probability of initiating dopaminergic therapy within the first year of their study. This observation suggested to the researchers that treatment with tricyclic antidepressants may delay the need to initiate dopamine therapy for Parkinson’s.
Is there any other evidence to support this finding?
Not directly (that I am aware of – and I am happy to be corrected on this).
But there was a study published back in 2002 which demonstrated a curious opposite effect caused by SSRIs:
Title: Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa.
Authors: van de Vijver DA, Roos RA, Jansen PA, Porsius AJ, de Boer A.
Journal: Br J Clin Pharmacol. 2002 Aug;54(2):168-70.
PMID: 12207636 (This article is OPEN ACCESS if you would like to read it)
In this study of the researchers wanted to look at the impact of SSRIs on the symptoms of Parkinson’s. To conduct this study, they selected all Levodopa users over the age of 55 years from the PHARMO prescription database (medical information from 2 million residents in the Netherlands). The analysis found that the initiation of SSRI therapy in Levodopa users was followed by a faster increase of anti-Parkinsonian drug treatment. It should be noted that this result was based on just 15 Levodopa users taking SSRIs, 31 Levodopa users taking tricyclic antidepressants, and 304 age-matched Levodopa users not using antidepressants. Thus, the result is some what under powered and needs to be independently replicated.
In addition, other research has suggested that depression and anxiety may be an independent risk factors for Parkinson’s (Click here and here to read more). Another study found that the initiation of any kind of antidepressant therapy was associated with a higher risk of being diagnosed with Parkinson’s within the first two years after initiation of treatment, but this could simply be a reflection of depression maybe being a risk factor by itself (Click here to read more about this).
So what did Prof Collier and his colleagues do next?
Their study suggested an effect, but it could not explain why this would be the case and so the researchers next turned their attention to better understanding what could be causing this delay.
And that effort resulted in this research report:
Title: Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of parkinsonism.
Authors: Paumier KL, Sortwell CE, Madhavan L, Terpstra B, Celano SL, Green JJ, Imus NM, Marckini N, Daley B, Steece-Collier K, Collier TJ.
Journal: Neuropsychopharmacology. 2015, 40(4):874-83.
PMID: 25267343 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers investigated whether long term treatment the tricyclic antidepressant – Amitriptyline – would have any neuroprotective in a neurotoxin (6-OHDA) model of Parkinson’s disease. The investigators treated the animals for 2 weeks before giving the neurotoxin and they found that the treatment resulted in a significant rescue of the dopamine neurons in the brain and prevented the motor-related behavioural problems associated with the model. The researchers also noted that Amitriptyline treatment increased the production of neurotrophic factors.
What is a neurotrophic factor?
A neurotrophic factor (neurotrophic = Greek: neuron – nerve; trophikós – to feed) is a chemical that is produced in the brain that helps to nourish the neurons and keep them alive. There are many different types of neurotrophic factors, but in this study the researchers were measuring just Brain derived-neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) – both of which have been found to support dopamine neurons (one of the populations of cell badly affected in Parkinson’s).
Amitriptyline treatment resulted in an increase in BDNF in the substantia nigra region both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. Amitriptyline treatment also resulted in an increase in GDNF levels but only before the neurotoxin was given.
Nervous that pre-treatment of Amitriptyline could be having an on dopamine processing, the investigators also investigated levels of the dopamine transporter (which helps to reabsorb used dopamine back into the cell) in animals that had had long term treatment with the anti-depressant (compared to untreated controls). They found no difference in dopamine transporter levels between the two groups, and so they concluded that the neuroprotective effect seen in their model was most likely due to the increase in BDNF levels.
This initial report was quickly followed up by a second study that supported these results:
Title: Tricyclic antidepressant treatment evokes regional changes in neurotrophic factors over time within the intact and degenerating nigrostriatal system.
Authors: Paumier KL, Sortwell CE, Madhavan L, Terpstra B, Daley BF, Collier TJ.
Journal: Exp Neurol. 2015 Apr;266:11-21.
PMID: 25681575 (This article is OPEN ACCESS if you would like to read it)
In this study, Prof Collier and colleagues conducted a time-course study to determine whether the tricyclic antidepressant Amitriptyline could cause changes in the levels of neurotrophic factors in relevant brain regions in both normal rats and those used to model of Parkinson’s (intrastriatal injection of the neurotoxin 6OHDA).
The researchers found that after continuous treatment of Amitriptyline to normal rats for 24 days, there was a significant increase in levels of both BDNF and GDNF in the substantia nigra region of the brain – where the dopamine neurons reside. In the rodents that were used in the modelling of Parkinson’s, there was a transient increase in supportive chemicals, which helped to reduce the progressive degeneration of dopamine neurons elicited by the neurotoxin.
All of these findings supported the investigators proposal that tricyclic antidepressants may have dual therapeutic value in Parkinson’s.
Interesting. So sunning up – what does it all mean?
No wait! We not finished yet.
This is where the story starts to get really interesting.
Following the publication of this neurotrophic study, the researchers in Michigan were contacted by Dr Peter Lansbury and Dr Craig Justman (from Lysosomal Therapeutics, Inc – a very interesting Boston-based biotech company that is taking a drug called LTI-291 to the clinic. LTI-291 is designed to increase the level of GCase enzyme activity in people with GBA-associated Parkinson’s – definitely the topic of a future blog post!).
Source: Lysosomal Therapeutics
Dr Lansbury and Dr Justman had experimental evidence that the tricyclic antidepressants Amitriptyline and Nortriptyline slowed the clustering (or aggregation) of the Parkinson’s-associated protein alpha synuclein. They had no intension of following up this interesting result as it was outside of the company’s focus, but they thought that Prof Collier and his colleagues may be interested.
Prof Collier and his colleagues had also contacted Dr Lisa Lapidus at Michgan State University and asked her to test Nortriptyline in her well characterised assay of anti-aggregation effects. She found that the tricyclic antidepressant (though she was not aware of what kind of compound she was testing) had potent anti-aggregation effects in her assay in a dose-related manner.
That’s validation, right?
The researchers expanded on these initial findings and published their results earlier this year:
Title: Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form.
Authors: Collier TJ, Srivastava KR, Justman C, Grammatopoulous T, Hutter-Paier B, Prokesch M, Havas D, Rochet JC, Liu F, Jock K, de Oliveira P, Stirtz GL, Dettmer U, Sortwell CE, Feany MB, Lansbury P, Lapidus L, Paumier KL.
Journal: Neurobiol Dis. 2017 Oct;106:191-204.
In addition to findings of Dr Lansbury, Dr Justman and Dr Lapidus described above (regarding the anti-aggregation properties of Nortriptyline), the researchers also treated aggregation-proned cells in culture with Nortriptyline and found reduced accumulation of alpha synuclein. They then tested Nortriptyline on dopamine neurons that produced very high levels of a mutant form of alpha synuclein protein (A53T) which eventually kills the cells. By exposing these cells being grown in cell culture to Nortriptyline, the researchers observed reductions in the number of cells dying (in a dose dependent manner).
Next the investigators turned their attention to the in vivo setting, and utilised both fly and mouse models of Parkinson’s to test Nortriptyline. The flies that the researchers used have very high levels of a mutant form of alpha synuclein protein (A30P), which results in neurodegeneration. By feeding the flies with Nortriptyline-supplemented food, the researchers reported a significant reduction in the amount of neurodegeneration observed. In mice that produced very high levels of human alpha synuclein protein (Line-D), the investigators started treating the mice with Nortriptyline daily for one month at 6 months of age. When they looked at the brains of these treated mice, they found that they had less alpha synuclein accumulation than the untreated group of mice.
Now, as if all of these experiments were not enough, Prof Collier and his colleagues decided to go yet further. They next utilised a rodent model of Parkinson’s that they had recently published:
Title: Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration.
Authors: Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ, Steece-Collier K, Kemp CJ, Celano S, Schulz E, Sandoval IM, Fleming S, Dirr E, Polinski NK, Trojanowski JQ, Lee VM, Sortwell CE.
Journal: Neurobiol Dis. 2015 Oct;82:185-199.
PMID: 26093169 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers injected rodents with alpha synuclein fibrils to model Parkinson’s.
What are alpha synuclein fibrils?
In its natural state, the Parkinson’s associated protein alpha synuclein is considered a monomer, or a single molecule. When it binds to other molecules, it forms an oligomer (a collection of a certain number of monomers in a specific structure). In Parkinson’s disease, alpha synuclein also aggregates to form what are called ‘fibrils’.
Microscopic images of Monomers, oligomers and fibrils. Source: Brain
Oligomer versions of alpha synuclein are emerging as having a key role in Parkinson’s disease. They lead to the generation of fibrils (and may even cause damage by themselves).
A hypothetical schematic of alpha synuclein in Parkinson’s. Source: Nature
It is believed that the oligomer versions of alpha-synuclein is being passed between cells – and this is how the disease may be progressing – and forming Lewy bodies in each cells as the condition spreads. For this reason, researchers have been looking for agents that can block the production of alpha synuclein fibrils and stabilize monomers of alpha synuclein.
In their previous study, the researcher injected rodents in a particular location of the brain with alpha synuclein fibrils, and then left the animals for up to 18 months to see what impact these proteins would have. They found cellular inclusions that had the characteristics of the features observed in the Parkinsonian brain (such as Lewy bodies). The rodents also demonstrated the loss of dopamine neurons. Thus, the investigators were excited about the possible use of these alpha synuclein fibrils to better model Parkinson’s and test new drugs… such as Nortriptyline.
Which brings us back to the research report from earlier this year.
Prof Collier and his colleagues tested the ability of Nortriptyline to reduce the effect of alpha synuclein fibrils to cause Parkinson’s-like damage. The alpha synuclein fibrils were injected into the brains of rodent, and two weeks later the rodents were randomly assigned to groups that received daily treatment of Nortriptyline or saline. This treatment was conducted for 6 weeks, and at the end of that period, the saline-treated animals exhibited the expected accumulation of alpha synuclein in the brain, while the Nortriptyline treated animals had consistently less aggregation.
In the image below, the alpha synuclein pre-formed fibrils (PFF) + saline treated animal has a lot more aggregated alpha synuclein (black dots diagonally across the image) than the PFF + Nortriptyline (NOR) treated brain.
The researchers also found that Nortriptyline was directly binding to alpha synclein and keeping it resistant to forming fibrils, thereby inhibiting pathological aggregation while also preserving its normal functioning. They concluded that Nortriptyline, “with a long history of safety and efficacy, may provide multiple benefits” for Parkinson’s, “including amelioration of comorbid depression, modulation of important signaling pathways involved in cell survival and plasticity, reduced inflammation and interference with misfolding and aggregation of alpha synuclein: a multi-function compound to treat a complex disorder”.
Is this some kind of wonder drug?
But wait, there’s still more.
In early 2016, an independent research group noticed something else about tricyclic antidepressants.
This observation involved L-dopa induced dyskinesias:
Title: Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats.
Authors: Conti MM, Goldenberg AA, Kuberka A, Mohamed M, Eissa S, Lindenbach D, Bishop C.
Journal: Pharmacol Biochem Behav. 2016 Mar;142:64-71.
In this study, the investigators wanted to compare three tricyclic antidepressants with graded affinity for two different types of cells: serotonin producing cells (SERT) vs. norepinephrine producing cells (NET). Both of these chemicals are neurotransmitters that help pass signals from one cell to another, but drugs can have different affinities for these cells. For example, the tricyclic antidepressant Clomipramine (affinity for SERT > NET), Amitriptyline (SERT = NET), and Desipramine (SERT < NET).
The researchers treated Parkinsonian rodents with high levels of L-dopa to induce dyskinesia. They then divided the animals into different groups and treated them with different doses of the three tricyclic antidepressants (plus L-dopa). Clomipramine, which has the highest affinity for SERT was most effective in reducing L-dopa-induced dyskinesia without altering L-dopa’s beneficial effects. In contrast, Desipramine, which has the highest NET affinity reduced the effectiveness of L-DOPA.
The researchers concluded that more work was required to understand the long-term effects of tricyclic antidepressant administration, and the mechanisms by which these drugs convey their effects.
So yeah, maybe this class of drugs is bordering on ‘wonder drug’ material. But all of this still needs to be tested in humans. We have ‘been to this rodeo’ many times before where drugs and compounds do amazing tricks in the lab, but fail to perform in the clinic.
Do you think I should start taking tricyclic antidepressant?
This is an obvious question to ask. And I know that I’m going to get a bunch of emails asking this exact question.
If I receive any emails of this nature, however, I will copy-and-paste in the following text:
“You will hopefully understand that I am very reluctant to give advice on such matters. This is for two reasons:
A. I am only a research scientist (not a clinician), and
B. Even if I was a clinician, it would be unethical for me to offer advice being unaware of the personal medical history/circumstances in each case”
Before considering any changes to one’s treatment regime, you should have a thorough discussion with your neurologist or a clinician that is familiar with your medical history. I certainly won’t be dishing out advice.
And please appreciate that all of this research (except for the first epidemiological studies) has been conducted in cells grown in culture and laboratory animals. As far as I am aware there has been no clinical testing of these drugs in Parkinson’s beyond testing their ability to reduce levels of depression (and again I am happy to be corrected on this).
All of this research is only on models of Parkinson’s. Source: Irishtimes
All of that said, I think that it would be useful for readers to point out a few things here with regards to the use tricyclic antidepressants.
As I mentioned near the top of this post, there are the side effects with tricyclic antidepressants usage (and this is partly why the treatment of depression in the wider public has shifted to SSRIs). Some are quite common side effects associated with tricyclic antidepressants, such as:
- Blurred vision
- Dry mouth
- Drop in blood pressure when moving from sitting to standing, which can cause lightheadedness
- Urine retention
While other less common side effects include:
- Increased appetite leading to weight gain
- Weight loss
- Excessive sweating
- Sexual problems, such as difficulty achieving an erection, delayed orgasm or low sex drive
Some of these side effects may be transient and disappear with time, while others can be more debilitating (and you should discuss changing medication with your physician). Side effects can also depend on the dose being used. And because different tricyclic antidepressants function in different ways, the side effects can vary somewhat from individual medication to medication. But there are a couple of common themes:
- Amitriptyline, Doxepin, Imipramine and Trimipramine are more likely to make you sleepy than other tricyclic antidepressants are.
- Amitriptyline, Doxepin and Imipramine are more likely to cause weight gain than other tricyclic antidepressants are.
- Nortriptyline and Desipramine appear to have better tolerated side effects than other tricyclic antidepressants do.
This information has been sourced from the MayoClinic which provides a lot more information on this topic.
Ok, so there are some side effects. Is there anything else to worry about?
There are also drug interactions that need to be considered when using tricyclic antidepressants. Below is a list of specific drugs that should not be used with the tricyclic antidepressant Amitriptyline (source: Drugs):
|Alcohol||Potentiates the effects of alcohol||Increased risks if overdose or suicide attempt occurs|
|Antiarrhythmics, class 1C (e.g., flecainide, propafenone)||Potential decreased amitriptyline metabolism||Monitor for TCA toxicity|
|Anticholinergic agents||Hyperthermia, particularly during hot weather, and paralytic ileus.||Use with caution; dosage adjustment may be needed|
|Anticoagulants (e.g., warfarin)||Possible increased prothrombin time|
|Antipsychotics (e.g., phenothiazines)||Hyperpyrexia, particularly during hot weather
Potential decreased amitriptyline metabolism
|Use with caution|
|Cimetidine||Potential decreased amitriptyline metabolism|
|Cisapride||Increased risk of QT interval prolongation and arrhythmias||Concomitant use contraindicated|
|CNS depressants (e.g., analgesics, antihistamines, barbiturates, general anesthetics, opiates)||Potentiates the effects of CNS depressants||Use with caution|
|Diazepam||Possible increased plasma amitriptyline concentration|
|Guanethidine and related compounds||Antagonizes the antihypertensive effects of guanethidine and related compounds|
|Levodopa||May interfere with levodopa absorption||Monitor levodopa dosage carefully|
|MAO inhibitors||Potentially life-threatening serotonin syndrome||Concomitant use contraindicated
Allow at least 14 days to elapse when switching to or from these drugs
|Methylphenidate||Possible increased plasma amitriptyline concentrations|
|Quinidine||Possible increased plasma amitriptyline concentrations|
|SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)||Possible serotonin syndrome
Potential decreased amitriptyline metabolism and increased plasma concentrations
|Use with caution; monitor for TCA toxicity
Allow at least 5 weeks to elapse when switching from fluoxetine
|Sympathomimetic agents (e.g., amphetamines, epinephrine, isoproterenol, norepinephrine, phenylephrine)||Increased vasopressor, cardiac effects||Use with caution; dosage adjustment may be required|
|Thyroid agents||Possible cardiac arrhythmias||Use with caution and under close supervision|
Of particular interest in this list are the common Parkinson’s treatments Levodopa (where Amitriptyline may interfere with levodopa absorption) and MAO inhibitors (which include MAO-B inhibitors like Rasagiline (Azilect) and Selegiline (Deprenyl, Eldepryl, Emsam, Zelapar) – use of Amitriptyline and MAO inhibitors could result in potentially life threatening conditions like Serotonin syndrome).
Feeling sufficiently warned? Let’s move on.
Have clinical trials of tricyclic antidepressants been conducted in Parkinson’s?
No. Not that I am aware (and again I am happy to be corrected on this).
But Prof Collier and his colleagues are apparently keen to rectify this and explore if these drugs could be having beneficial effects clinically.
So what does it all mean?
Depression is a terrible problem that affects a certain portion of the western world population to varying degrees. One of the classes of drugs that is used in the treatment of depression has recently been shown to have potentially beneficial effects in models of Parkinson’s.
While a treatment that both alleviates depression (affecting about 1/3 of the Parkinson’s community) AND potentially slows Parkinson’s would be extremely positive for affected individuals, it is still necessary to conduct randomised clinical trials of these drugs to determine for whom they are beneficial (everyone is different it seems with PD) and to what extent they have an effect (is it simply a short term effect?). Until such research has been conducted, it is difficult to assess how these drugs can be used in the treatment of Parkinson’s.
Phew, long post!
And one last word on depression: In my home country of New Zealand, the indigenous people – the Maori – have a phase: Kia kaha (pronounced “Key-a Ka-ha”).
It basically translates to ‘stand strong’.
I have a close friend as well as a family member affected by depression of varying severity, and in both cases there has always been a mental effort by those individuals to stand strong.
When faced with a terrible adversary, it really does not matter whether you win or lose, kia kaha.
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The banner for today’s post was sourced from Phase2therapy