Since 1990 TCA antidepressants are replaced with SSRI antidepressants. With relatively the same level of effectiveness, SSRIs are safer than TCAs. However, SSRIs have side effects that may affect your treatment.
Tolerability and side effects are different, but very closely related concepts. One of the main reasons for stopping treatment with antidepressants is the severity of their side effects. 43% of people with depression stop taking antidepressants due to side effects. Patients taking TCAs are more likely to discontinue treatment and experience more side effects than patients taking SSRIs.
More information about the main side effects:
Bleeding
– SSRIs are thought to influence hemostasis by affecting the uptake of serotonin by platelets. The more strongly antidepressants act on serotonin uptake, the higher the risk of bleeding. This applies to SSRIs and venlafaxine, the antidepressant with the most potent serotonergic effect of the SSRI group.
– SSRIs increase the risk of gastrointestinal bleeding.
– The risk of bleeding is increased by SSRIs, but not by TCAs.
– The risk of bleeding increases the simultaneous use of SSRIs and aspirin, SSRIs and non-steroidal anti-inflammatory drugs.
What to do if antidepressants don't help?
First of all, don’t panic. For some patients, antidepressants begin to help literally from the first days, but this is not always the case. In most cases, improvement occurs after weeks. An antidepressant is not a headache pill that works immediately after taking it. It is important to take them regularly, in the doses prescribed by your doctor.
Medicines may cause some side effects at first. For example, people who have just started taking SSRIs may experience headaches, nausea, dry mouth, and bowel dysfunction. After a period of adaptation, these symptoms disappear.
If the side effects are very strong, persist for too long, if you have been taking the drug for several weeks, but do not feel any improvement, you should not engage in amateur activities, consult your doctor.
Side effects on the cardiovascular system
– SSRIs were originally introduced as a safe alternative to TCAs. Recently, there is emerging evidence that SSRIs produce cardiovascular side effects, such as prolonging the QT interval, thereby increasing the risk of ventricular arrhythmias. However, TCAs prolong the QT interval more significantly than SSRIs. Among the SSRIs, citalopram has the strongest effect on the QT interval.
– TCAs are more likely to cause cardiovascular adverse reactions than SSRIs; Mirtazapine has a very low risk of these types of side effects; SSRIs have the highest risk of increasing blood pressure; among SSRIs, venlafaxine (at a dosage of 150 mg/day) has the highest risk of increasing blood pressure; Increased blood pressure due to SSRI use is very rare.
– All antidepressants except SSRIs increase resting heart rate and reduce heart rate variability; This effect is most significant when taking TCAs.
How do you know which antidepressant is best to start with?
Initially, the doctor prescribes the drug that, in his opinion, is best suited for a particular patient. It is impossible to know for sure what will work more effectively, but there are some factors that you can focus on: the type and symptoms of depression, side effects of medications, the general health of the patient, and concomitant diseases.
If you have family members with depression and certain medications work well for them, chances are the same medications will work for you.
Antidepressants can be prescribed during pregnancy and breastfeeding, but with caution. The doctor must carefully weigh the possible risks.
Hepatotoxicity
– The weakness of MAO and TCA antidepressants was considered to be their hepatotoxicity. Recent research confirms this idea and, in addition, shows the presence of a risk of hepatotoxicity with new antidepressants.
– The risk of hepatotoxicity is relatively higher when taking nefazadone, bupropion, duloxetine, agomelatine; the risk is relatively lower when taking citalopram, escitalopram, paroxetine, fluvoxamine.
– In the TCA group, clomipramine and amitriptyline have high hepatotoxicity.
– Agomelatine has the highest risk of hepatotoxicity.
– Milnacipran increases the risk of hepatotoxicity more significantly than duloxetine.
– SSRIs, compared with other antidepressants, do not significantly increase the risk of hepatotoxicity.
Convulsions
– Bupropion is considered the riskiest drug for seizures. But a lot depends on the dosage form. Bupropion IR (immediate release) at a dose greater than 450 mg increases the risk of seizures by 10-fold. Bupropion SR (extended release) at doses up to 300 mg increases the risk of seizures by only 0.01-0.03%. The same slight increase is observed when taking SSRIs.
– TCAs have a higher epileptogenic potential than bupropion, so antidepressants of this group are contraindicated in patients with a predisposition to seizures.
– Current research complicates the understanding of the risk of seizures. New evidence suggests that all antidepressants appear to increase the risk of seizures.
– The riskiest antidepressants: trazodone, lofepramine, venlafaxine. In the SSRI group, the greatest risk is when taking paroxetine and citalopram, the lowest when taking escitalopram and sertraline.
– According to other data, SSRIs are more dangerous than TCAs and the highest risk of seizures occurs when taking sertraline.
– Large studies, however, show that grand mal seizures occur more often in patients taking TCAs rather than SSRIs.
Antidepressants: why can we be wrong about their effectiveness and safety?
Introduction
Depression is becoming one of the most common diseases that worsens the quality and length of life, as well as leading to disability.
[1] These factors predetermine the search for means for the prevention and treatment of depressive disorders. Among them, there are medicinal and non-medicinal methods of therapy. Due to the duration and high cost of psychotherapy, which is the main non-drug treatment for depression, doctors and patients often tend to treat this disorder with antidepressants. [2] Classified into different drug classes according to their mechanism of action, antidepressants are widely used in the treatment of so-called major depressive disorder, formerly called depression.
Currently, the debate about the effectiveness and safety of antidepressants continues. [3] Meta-analyses are used to evaluate the totality of data obtained in studies, however, they do not allow us to give an unambiguous answer about the balance of benefits and harms with long-term use of antidepressants.
The challenge is that psychiatry is a specialized area of medicine that lacks reliable biomarkers of mental illness and a primary endpoint to summarize safety and effectiveness. [4] The analysis of the benefits and risks of prescribing drug therapy in psychiatry differs from other therapeutic areas.
Although meta-analyses generally support the use of antidepressants as an effective and relatively safe treatment for depressive disorder, concerns about the effects of these drugs continue to exist among both researchers and patients. [4] This review examines the most common shortcomings of studies and meta-analyses of data on the use of antidepressants, which contribute to the exaggeration of their effectiveness and insufficient assessment of the risks of therapy.
Unclear mechanism of action
One of the main reasons for doubts about the effectiveness and safety of antidepressants is the lack of understanding of their exact mechanism of action. A common explanation for the need to take these drugs is the idea that they compensate for the deficiency of certain substances in the brain. This hypothesis is more than 50 years old, and it implies a violation of serotonergic, noradrenergic and dopaminergic neurotransmission as the basis for the pathogenesis of depression. [5]
However, later numerous refutations of this idea about the mechanism of development of depressive disorder were received, and the hypothesis has long been recognized as erroneous. Thus, a deficiency of the neurotransmitter dopamine causes Parkinson's disease, but antidepressants that promote its accumulation do not help in the treatment of this disease. Because of this, scientists and clinicians currently avoid classifying depression based on a deficiency of any of these three amines. [6]
Biochemical processes in the brain are an extremely complex and not fully understood mechanism. For this reason, it is impossible to obtain data on the decrease in the levels of serotonin and other amines in the central nervous system in depression by studying their concentrations in blood serum. Studies of antidepressants also cannot evaluate the direct effect of drugs on the biochemistry of the human brain and compare changes in certain indicators on the psyche in the long term. [6]
Unbalanced methods for assessing the benefits and risks of therapy
It is known that an event that occurs after taking a drug does not always mean that it occurred as a result of taking it. The severity of depressive symptoms can spontaneously change for better or worse, and the start of an antidepressant course may coincide with one of these periods. For this reason, it remains unclear whether the subsequent reduction in clinical manifestations of depression is caused by the effects of drugs or occurs after an exacerbation.
In the absence of biochemical markers of diseases, diagnostic scales have become widespread in psychiatry. They are used both to identify certain disorders and to evaluate the effectiveness of therapy. The most popular among them are the Montgomery-Osberg scale (assesses 10 symptoms of depression) and the Hamilton scale (includes 17 symptoms). [4]
Because scales are rarely used to study side effects, studies may tend to overestimate the benefits and underestimate the risks of antidepressants. The effectiveness of antidepressants becomes statistically higher if depressive symptoms are assessed together as part of a scale and decreases when they are assessed separately. On the contrary, side effects in studies are usually classified separately, which creates the preconditions for reducing their significance. [7]
The Montgomery-Osberg Depression Rating Scale (score range 0–60) is a relatively sensitive tool for assessing changes induced by antidepressants. The FDA approved the antidepressant esketamine in 2021 based on a 20-point reduction on the Montgomery-Osberg scale with the drug, compared with 16 points in the placebo group. However, the 4-point difference between the two groups only reached significance at p < 0.05 when a one-sided p value was used. [8]
Another study of esketamine demonstrated, based on the summation of the positive effects of therapy, improvement in 61% -75% of patients. Statistical assessment of adverse events, including suicidal thoughts and behavior, cognitive impairment, increased blood pressure, and others, was carried out separately and not summarized. Thus, there was a single endpoint for assessing the benefit of the drug, but safety was analyzed as a composite of symptoms without reduction to a single denominator, which reduces the likelihood of detecting statistical differences and leads to asymmetric risk-benefit analysis. [9]
Despite the subtle differences between the groups and the lack of evidence that the drug's benefits were maintained across treatment, the FDA's approval of esketamine was accompanied by widespread press coverage, with the drug being hailed as a "first-in-class" drug. [8]
Lack of methodological rigor
While expert opinion has ceased to be an important tool in the new paradigm of medical data analysis, meta-analysis, a convenient and accessible tool for evidence-based medicine, can in some cases serve as a marketing tool for promoting certain drugs. [10]
Over the past decade, approximately 200 meta-analyses evaluating the effectiveness of antidepressants have been published. The authors of many of them had a conflict of interest, some of them did not hide this fact. Most meta-analyses, as expected, contain virtually no negative conclusions in the abstract, which summarizes the findings of the work on the effectiveness of antidepressants. [10]
Two recent systematic reviews and meta-analyses, one of which assessed the effectiveness of 21 antidepressants from different drug classes, the other of selective serotonin reuptake inhibitors (SSRIs), found statistical, but not clinical, differences compared with the placebo group. [11, 12]
The first meta-analysis, published in The Lancet, included 522 scientific papers involving more than 116 thousand patients. The authors concluded that all antidepressants were more effective than placebo. Less significant differences between drugs were found when placebo-controlled studies were included in the analysis, while in experiments without placebo and blinding of the results, there was greater variability in the effectiveness and tolerability of therapy. [eleven]
The disadvantage of this meta-analysis, according to some scientists, is insufficient attention to such a phenomenon as systematic error (bias), which can distort the conclusions. Among other things, factors such as selective reporting and reasons for exclusion from studies were not analyzed. In addition, evaluation of the effectiveness of therapy was limited to 8-12 weeks, while the course of treatment with antidepressants usually lasts several years. [4, 13]
There were also methodological limitations to the meta-analysis of SSRIs. Among the outcomes studied, there is virtually no data on suicidal behavior, quality of life, or long-term consequences of therapy. [4, 12]
Thus, based on the systematic meta-analyses, it cannot be reliably stated that antidepressants cause clinically significant improvements in depression, although this is the main purpose of their use.
No research = no result?
Meta-analysis serves as a tool for examining a collection of data from different studies. One way to improve the results of a drug study is to exclude negative results. [14, 15] Many scientific papers with negative results are not published. This is believed to be due to the lack of significant contributions to science and the low interest of journals in such publications.
At the same time, journal reviewers often do not review the entire study protocol, and published claims of a drug's effectiveness are often greater than those reported in the study's primary endpoint. [4]
Thus, negative results of an antidepressant study must be included in the analysis of the risk-benefit ratio of taking these drugs. The challenge is to incorporate all available data into a meta-analysis.
According to Ben Goldacre, a famous British scientist and author of several books, about half of the studies on antidepressants do not meet the EU requirements for registration of their results. A critic of the work of pharmaceutical companies, Goldacre points out that negative results and failed developments may never be reported. [16]
However, the lack of effect of the drug is also a kind of achievement and sometimes the detected effects can become the main indication for use, which happened with varenicline and sibutramine, which did not demonstrate an effect on the course of depression. [17]
Limited data on the safety of antidepressants
Long-term use of any drug is associated with many concerns regarding its safety profile. The impact of antidepressants on a person’s mental state makes one think about the appearance of side effects with long-term use of these drugs, as well as the likelihood of developing dependence on them.
Scientific evidence supporting long-term maintenance treatment with antidepressants is based almost exclusively on relapse prevention studies. These long-term studies are primarily discontinuation trials in which antidepressant users in remission are randomized to receive either an antidepressant or placebo replacement. Differences in relapse rates between groups are then assessed to reflect the preventive effect of the drug. The results of these trials are generally positive and consistently show that after about 12 months, the relapse rate is approximately 40% for those participants who were switched to placebo and 20% for those who remained on active treatment. [18]
This provides the scientific basis on which experts base their recommendations for long-term antidepressant treatment. At first glance, these results are truly impressive.
Researchers from the Cochrane Center asked how a drug with limited effectiveness in treating acute depression could have such impressive preventative effects. Is it possible that these results are a methodological artifact? They ultimately concluded that "Taken together, the data do not support definitive conclusions regarding the effectiveness of antidepressants for depression in adults, including whether they are more effective than placebo for depression." [18]
Moreover, study protocols other than cessation of prophylactic treatment did not provide reliable evidence of significant long-term benefits of antidepressant therapy. [19-21] This prompted S.N. Ghaemi, lead investigator from Tufts Medical Center in Boston, Massachusetts, concluded that the long-term preventive effectiveness of antidepressants for recurrent unipolar major depression remains uncertain. [22]
Some studies suggest a correlation between the use of antidepressants and the increasing prevalence of mental disorders. The mechanism of this phenomenon remains not fully understood. According to scientists' assumptions, this relationship is based on persistent changes in biochemical processes in the central nervous system. [23]
Various authors have emphasized that long-term use of antidepressants promotes neurochemical adaptation and, as a consequence, provokes physical dependence and then a withdrawal reaction when the dose is reduced or discontinued, comparable to the withdrawal of other drugs that act on the central nervous system (benzodiazepines, psychostimulants or opioids). [24-27]
More than half of people who try to stop taking antidepressants report experiencing adverse events during withdrawal. Many of the effects indicated in the instructions turn out to be more severe than described. [28]
Withdrawal symptoms include, but are not limited to, anxiety, panic attacks, irritability, aggression, lethargy and flu-like symptoms, electric shock sensations, dizziness, tremors, crying spells, suicidal thoughts, insomnia, anorexia, and nausea. Many of these are easily mistaken for relapse of depression, which is assessed using scales that cannot distinguish withdrawal from relapse. [29]
Withdrawal reactions can be so significant that they are classified as relapse of depression in 27% of patients within 5-8 days of double-blind placebo treatment cessation. [30-31]
Such reactions may ultimately lead to a return of the original symptoms with greater intensity or persistent long-term disorders associated with decreased responsiveness to therapy. [32]
While the former usually occur within a few days of discontinuation of the drug and resolve spontaneously within 6 weeks, persistent antidepressant withdrawal symptoms may have a delayed onset and continue for months and sometimes years. [33-34]
This problem is receiving attention in many countries: research groups are being created to study drug dependence, patients are completing individual reports of unwanted effects during treatment withdrawal. Despite the fact that these medical and public control measures are being taken, there are concerns that problems with the withdrawal of antidepressants are not fully reflected in the instructions for the drugs.
Questions about the safety of antidepressants in older people
There is concern about the use of antidepressants in older people, for example due to senile depression. Some of these drugs have an anticholinergic effect, while changes in cholinergic regulation are observed in dementia. In a study by Coupland et al. assessed whether exposure to anticholinergic drugs, including antidepressants, was associated with the risk of dementia in 58,769 patients diagnosed with dementia and 225,574 controls over 55 years of age. Prescription information for drugs with potent anticholinergic effects was used to calculate measures of cumulative anticholinergic exposure. Data was analyzed from May 2016 to June 2021. Finally, exposure to several anticholinergic drugs was associated with an increased risk of dementia. The results were especially significant in people over 80 years of age. The results obtained emphasize the importance of competent prescription of anticholinergic drugs in middle-aged and elderly people. [35]
In another study, the same group of authors examined side effects among older people taking antidepressants. These included all-cause mortality, suicide attempts and self-harm, cardiovascular complications, falls and fractures, upper gastrointestinal bleeding, epilepsy and seizures, and road traffic accidents. The analysis was conducted with adjustments for variables that may confound the results. Risk ratios were calculated for antidepressant class (tricyclic and related antidepressants, SSRIs, other antidepressants), dose, and duration of use.
As a result, SSRIs and drugs from other classes of antidepressants have been associated with an increased risk of serious side effects such as death, falls, fractures, strokes and seizures. Because this is an observational study, it is subject to bias and bias, which is an important limitation. The scientists concluded that further research is needed to confirm these results, but despite all the limitations, the risks and benefits of such therapy should be carefully assessed when prescribing antidepressants to older people. [36]
conclusions
The use of antidepressants around the world is growing every year, with the average course of taking them reaching 12 months or more. However, rates of mental health disability or suicide, the most serious adverse outcome of depression, remain high. If antidepressants were effective, treatment would be expected to reduce these levels. [37]
Despite this discrepancy, global sales of antidepressants exceeded $10 billion a year within a few years. Open and hidden advertising of antidepressants without reference to strict indications for their use contributes to the fact that many people begin to see drug therapy as a source of solution to all problems. [38]
Given the limitations in effectiveness and long-term safety concerns of these drugs, their rational use requires further study. It is necessary to increase the awareness of physicians involved in the prescription of antidepressants regarding when and in which patients therapy should be started, taking into account the risk and benefit perspective of taking a particular drug.
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17. Harrington D, D'Agostino RB, SrGatsonis C, etal. New guidelines for statistical reporting in the journal. N Engl J Med 2019;381:285-6.
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Suicide
– The FDA in 2004 required manufacturers of antidepressants to place a warning on their packaging about the increased risk of suicide in children and adolescents. The controversy of this rule is that the disease, which is treated with antidepressants, itself increases the risk of suicidal behavior. Limited data on the association of antidepressant use with suicide attempts still does not allow us to draw a clear conclusion.
– A relative increase in suicide risks is observed with venlafaxine, escitalopram, imipramine, duloxetine, fluoxetine and paroxetine.
Overdose safety
– Among those who commit suicide, the most common mental disorder is depression. One in four patients with depression attempts suicide. For this reason, the safety of higher doses of antidepressants is very important.
– The highest hazard index (number of deaths per thousand poisonings with antidepressants) is for amoxapine, maprotiline, and desipramine. All SSRIs and SSRIs have a lower hazard index than TCAs.
– The proportion of deaths in the total number of poisonings for SSRIs is less than for venlafaxine and mirtazapine.
Literature:
- Pharmacology of antidepressants / I. A. Vinogradova, V. D. Yunash, S. V. Goranskaya, etc.; Ministry of Science and Higher Education of the Russian Federation, Federal State Budgetary Educational Institution of Higher Education "Petrozavodsk State University". — Petrozavodsk: PetrSU Publishing House, 2020. – 36 p.
- Psychotropic drugs: reference book. practicing physician / F. Bochner et al.; scientific ed. rus. ed. Yu. A. Alexandrovsky; lane English A. N. Redkin. - Moscow: Litterra Publishing House, 2006. - 292 p.
- A short reference book on psychopharmacology, pharmacotherapy and mental pathology / Kozlovsky, Vladimir Leonidovich. — St. Petersburg: SpetsLit, 2015
Sexual dysfunction
– Sexual dysfunction in patients with depression is caused by the disease and the medications prescribed to treat it. All antidepressants that affect serotonin or norepinephrine uptake cause sexual dysfunction. There is no evidence that SSRIs and SSRIs are less effective in this area than TCAs.
– The most common causes of sexual dysfunction are citalopram, fluoxetine, paroxetine, sertraline and venlafaxine. Imipramine is the same, but weaker than the five named antidepressants.
– Bupropion has the weakest sexual side effects compared to other modern antidepressants.
Weight gain
– Previously, it was believed that SSRIs and SSRIs contributed to excess weight gain. Among the SSRIs, the riskiest in this regard is paroxetine, and among the TCAs, amitriptyline. However, on average, weight gain occurs similarly with amitriptyline, sertraline, and fluoxetine.
– SSRIs and SSRIs may be associated with weight loss. After 4 months of treatment, this effect disappears, and paroxetine begins to contribute to the gain of extra pounds.
– Amitriptyline and mirtazapine promote weight gain in short-term and long-term treatment.
– Imipramine and bupropion promote weight loss or relatively slow weight gain in short-term and long-term treatment.
– In general, the latest evidence suggests that weight gain occurs to some extent when taking all antidepressants.
Hyponatremia, sleep disturbances, sweating
– The first reports of hyponatremia due to antidepressants involved TCAs. But the risk of hyponatremia is higher with SSRIs than with TCAs.
– The highest risk in the SSRI group is citalopram and escitalopram.
– Venlafaxine has the same risk as SSRIs or higher.
– The risk of hyponatremia when taking antidepressants increases in elderly patients and in cases of concomitant use of diuretics.
– The effect of antidepressants on sleep can vary greatly. The duration of sleep may be reduced, or it may be increased.
– Venlafaxine reduces the REM sleep phase, which is why it is prescribed in the treatment of narcolepsy.
– Many TCAs have a very strong sedative effect.
– Bupropion may cause insomnia.
– Increased sweating occurs with TCAs, SSRIs, and SSRIs.
– Sweating is observed in 10% of patients taking SSRIs, venlafaxine, TCAs.
How does the central nervous system work?
The central nervous system (CNS) “leads the parade.” It includes the spinal cord and brain, and is responsible for simple and complex reflexes - standard reactions to any influence. All this works with the help of nerve signals - impulses.
The nervous system consists of many nerve cells called neurons. In order for neurons to conduct nerve impulses, they must be connected into a network that will transmit the impulse from one cell to another. Imagine children passing a ball to each other in gym class. Children are nerve cells connected into a system, and the ball is a nerve impulse. But the hands with which children pass the ball are a synapse, a point of contact.
At synapses, nerve impulses are transmitted from one cell to another. This happens with the help of neurotransmitters - these are intermediary substances. Accordingly, if there are not enough neurotransmitters, then the impulses will pass poorly. This means that the functioning of the entire body will be disrupted: after all, the nervous system controls everything.
In addition, there is one more nuance. Neurotransmitters are substances of different natures, in particular, norepinephrine, serotonin and dopamine are among them. These substances are hormones. Therefore, in addition to transmitting nerve impulses, they also perform many functions as hormones. They affect the functioning of individual organs and systems, the processes of contractility of muscles, blood vessels, and partly, mood and internal sensations. And with depression, a person’s level of these neurotransmitter hormones often decreases. That’s why it’s so difficult for patients: feelings of anxiety, apathy and worthlessness are caused by a lack of serotonin, dopamine and norepinephrine. And since hormones affect many other functions of the body, this explains the physical manifestations of depression - weakness, fatigue, unstable appetite.
Antidepressants precisely influence the level of these neurotransmitter hormones: they block their breakdown or uptake by neurons. This increases their level.
