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The trouble with antidepressants: why the evidence overplays benefits and underplays risks—an essay by John B Warren

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• Peer review
• John B Warren , director
• Medicines Assessment, Ipswich, Suffolk, UK
• jbwarren5{at}gmail.com

Widespread prescribing has not reduced mental disability or suicide, raising questions about the assessment of evidence on effectiveness and safety of antidepressants, writes John Warren

Depression can be severe and reduce life expectancy. Antidepressant prescribing has increased substantially in recent years so that one in eight UK adults, some 7.3 million people, now receive a prescription for antidepressants each year, and many take them long term. 1 More than 60% of US residents taking antidepressants do so for more than two years. 2

Although meta-analyses seem to support widespread use, concerns have been raised about the effectiveness and safety of the drugs. The conclusions of meta-analyses have been criticised because of manufacturers’ influence on trials, 3 4 under-recognition of the placebo effect, inadequate attention to negative data, different methods used to assess risk and benefit, and lack of benefit on suicide. There are also concerns about limited safety databases and the huge commercial promotion of these drugs.

Analysis of the benefits and risks of drugs in psychiatry differs from other therapeutic areas. There are no reliable biomarkers of psychiatric disease and no primary endpoint to summarise safety and efficacy (an equivalent to mortality in cardiovascular or oncology trials). Psychiatry therefore depends on composite scales for diagnosis and to assess drug efficacy. As composite measures are rarely used for adverse events, trials are likely to overestimate benefit and underestimate risks, with serious implications for public health. Although prescribers will often see patients improve over time, questions remain about how much antidepressants contribute to this and whether long term treatment is safe.

Unclear mechanism of action

A common justification for using antidepressants is that they correct a chemical deficiency in the brain. The monoamine hypothesis, over 50 years old, implicates serotonergic, noradrenergic, and dopaminergic neurotransmission in the pathogenesis of depression.

Deficiency of the neurotransmitter dopamine explains Parkinson’s disease, but no similar chemical deficiency has been shown in the human brain for depression, the biochemistry of which remains complex and unexplained. 5 6 Depression has no subclassification depending on which of the three amines is deficient, even though each amine differs in its pharmacology and physiology.

The limitations of the monoamine hypothesis are widely accepted in terms of drug efficacy, though altered monoamine neurotransmission remains relevant to much of the safety profile of antidepressants. But composite endpoint safety data from long term trials does not have sufficient sensitivity to fully document the effect of these alterations in brain biochemistry on the psyche. This includes quantifying neurophysiological adaptation to long term treatment.

Promotion of small effects

Symptom severity fluctuates spontaneously during depression, and antidepressants started during exacerbations can appear to be more successful than they are. In a typical 6-12 week trial, scores among participants in the placebo arm fall from a mean of roughly 25 to 12-15 on the widely used Hamilton Depression Rating Scale. Any additional effect of active treatment is usually of questionable clinical importance.

A cycle of enthusiasm for the latest drug, big pharma’s large promotional budgets, and the delayed recognition of risk recurs throughout the history of pharmacology. Past examples in psychiatry include morphine, heroin, insulin, metronidazole, chloral hydrate, bromides, hyoscine, barbiturates, amphetamines, and major tranquilisers.

Esketamine, although not a typical antidepressant, is a recent example of how limited evidence for a new drug can attract favourable publicity. 7 The trials used the Montgomery-Åsberg Depression Rating Scale (score range 0-60), which is more sensitive to changes induced by antidepressants than the Hamilton scale. The US Food and Drug Administration approved esketamine in 2019 8 based on a finding of a 20 points reduction with esketamine compared with 16 points with placebo in the first 28 days of treatment. 8 Most of the reduction in the esketamine arm was also seen with placebo. The four point difference between drug and placebo reached a significance of P<0.05 in some trials only if a one sided P value was used. 9 Despite these small changes and no evidence of a persistent, clinically relevant, benefit, the FDA approval was accompanied by press coverage 7 and the drug heralded as a “first in class” treatment in the New England Journal of Medicine . 9

The small effect sizes reported for antidepressants are often further reduced after a drug is marketed. This was the fate of reboxetine, 10 11 authorised in the UK in 1997. The effectiveness of reboxetine was analysed by remission and responder rates, which do not translate directly into clinical significance. Reboxetine was ineffective in mild or moderate depression. A post-hoc analysis showed a statistically significant treatment effect on response rate for severe depression, though not a clinically significant benefit in symptom rating scales. 10 A former FDA employee noted the full set of data, on which the FDA had based a negative opinion for reboxetine, is not publicly available. 12

Meta-analyses and mean differences

Two recent systematic reviews and meta-analyses—one examining 21 common antidepressants 13 and the other selective serotonin reuptake inhibitors (SSRIs) 14 —found statistically, but not clinically, significant effects. Both attracted publicity that promoted antidepressant use 15 despite criticisms of the analyses. 16 17 18 19 20

Unblinding from adverse events may have contributed to the 0.3 standardised mean difference in effect size seen with antidepressants 13 and the mean difference of <2 on the Hamilton scale with SSRIs. 14 Standardised mean difference compensates for different rating scales, and a minimum of difference of 0.5 has been recommended for clinical significance. 21 A 2004 guideline from the National Institute for Health and Care Excellence (NICE) proposed a minimum of three points for a clinically significant difference on the 52 point Hamilton scale. 22 Even a three point change may be too low a threshold, 23 because it is undetectable by clinicians. 24

The spontaneous variability of the disease within the study population means that both placebo and active treatment patients can sometimes be classified as responders. It is the mean difference between the two groups that defines the treatment effect; it is not valid to say some individuals have responded to treatment, as this cannot be distinguished from background fluctuation in symptoms.

No evidence shows that increasing antidepressant dose increases the response in severe depression (standardised mean difference 0.05; 95% confidence interval −0.14 to 0.25). 25 Higher doses have been linked to violence, suicidality, homicide, mania, and psychosis. 26

The Oxford meta-analysis of 21 antidepressants did not sufficiently account for bias, selective outcome reporting, or reasons for attrition. 16 17 18 19 20 Efficacy analysis was restricted to 8-12 weeks’ treatment, though treatment for years is common. For the SSRI meta-analysis, there were almost no data on suicidal behaviour, quality of life, and long-term effects. 14 A reasonable conclusion of systematic meta-analyses is that antidepressants do not cause clinically significant improvements in depression.

Missing negative data

Meta-analyses depend on data from systematic reviews, 27 but to be reliable they need to dig into regulatory datasets to find the data. 3 21

The more compounds that are developed, the greater the chance of a false positive result. Less than half of antidepressant trials submitted to the FDA have positive results, 3 28 but many more trials with negative findings are not submitted. Journals rarely check protocol endpoints, and published claims of efficacy are often greater than the effects observed on the protocol specified primary endpoint. 29 When antidepressants are approved, negative data can be overlooked, as with vilazodone in 2011, when two positive trials were mentioned in the FDA label and five negative trials omitted. 29 Negative results must be included in risk-benefit analyses, as shown by the case of reboxetine. 10 11

It is a challenge to ensure meta-analyses consider all available data. Many negative trials of antidepressants are not publicly available, 25 26 28 and about half of trials do not comply with EU requirements to register their results. 30

Negative trials may be submitted to regulators under conditions of confidentiality. Trials from failed developments may never be submitted. 17 Some drugs developed for depression, such as sibutramine or varenicline, have been approved for other indications after trials in depression failed. Meta-analyses consider the influence of multiplicity on statistical significance; this is important as more than 20 P values can be reported for a single trial. 31 But meta-analyses cannot consider the influence of multiplicity for trials whose results are not available, or for drugs where a failed development means they are no longer classified as antidepressants, even though their results may cast doubt on a class benefit.

Unbalanced methods for assessing benefit and risk

Psychiatry depends on composite endpoints for the diagnosis and monitoring of mental illness. The Montgomery-Åsberg scale measures 10 symptoms, and the Hamilton scale a minimum of 17. Were these symptoms assessed separately, no trial of efficacy would reach statistical significance. By contrast, adverse events are categorised separately and rarely made into a composite.

The safety database submitted for esketamine approval was unusual as it included a composite to assess dissociation, the Clinician-Administered Dissociative Symptoms Scale. The assessment showed that 61%-75% of patients with current treatment developed dissociative or perceptual changes. Other safety indicators, including misuse, suicidal thoughts and behaviours, increased blood pressure, cognitive impairment, and cystitis were measured separately and not summarised in a composite. An incidence of at least 5% and at least twice that of placebo was reported for dissociation, dizziness, nausea, sedation, vertigo, hypoaesthesia, anxiety, lethargy, blood pressure increase, vomiting, and feeling drunk. 8 Whereas one primary endpoint was used to summarise benefit, safety was analysed as a collection of symptoms with no single endpoint, mitigating against finding statistical significance 32 and leading to the asymmetrical analysis of risk and benefit. 33

Limited safety data

Concerns raised by patient representatives about dependence, safety, and the level of prescribing led the UK All-Party Parliamentary Group for Prescribed Drug Dependence to examine the evidence on withdrawal problems with antidepressants. 34 35 More than half of people who attempt to stop taking antidepressants reported withdrawal effects; almost half of the reported effects were severe and some lasted for weeks or months. Many patients have made individual reports of withdrawal adverse events, though such reports have been criticised for a lack methodological rigour. 36 Nonetheless, there is concern that patients’ experiences of withdrawal problems are not fully reflected in drug information labels. 37 38

Data from the US, UK, Australia, Denmark, Iceland, and Sweden suggest a correlation between the use of antidepressants and the increasing prevalence of mental disability. Antidepressants might increase the risk of chronic depression, the incidence of conversion from a unipolar to bipolar disorder, and the chance of being classified disabled. 39

Long term use may propel the illness to a more malignant and unresponsive course, 40 possibly triggered by changes in brain biochemistry. 41 Since 1966 there has been concern that antidepressants might shorten the intervals between depressive episodes; about 6% of patients are in remission after 12 months’ treatment compared with about 85% in control groups. 39 The involvement of the cholinergic system in several types of dementia raises concern about the long term anticholinergic effects of many antidepressants. 42

An observational study of antidepressant use among older people found increases in serious adverse events such as death, falls, fractures, strokes and seizures. 43 Despite the study’s weakness, serious morbidity and mortality cannot be excluded as a consequence of antidepressant treatment of older people.

Inconsistencies

Many prescribers consider their accumulated clinical observations of individual cases proves the efficacy of antidepressants. Given the long established use of these drugs, it might be expected that the level of prescribing would now be stable. Yet the use of antidepressants in the UK has doubled in the past decade, and most are taken for more than a year. This has not reduced the rate of mental disability, or suicide—the most serious outcome in depression. If antidepressants were effective it might be expected that treatment would reduce the suicide rate, or at least suicide ideation.

A review of esketamine describes how a third of patients with treatment resistant depression attempt suicide 9 but does not discuss the effect of the drug on this endpoint. This is despite the fact that three patients who received the drug died by suicide during trials, compared with none in the control group. 7 The FDA label describes a non-significant increase in suicidality, recommending that patients who experience emergent suicidal thoughts or behaviours should stop treatment. 8

Public health concern

Given limited efficacy and long term safety concerns, the current level of UK prescribing is a major public health concern. Widespread prescribing is supported by short duration trials using composite endpoints designed to detect minor changes in efficacy, enthusiastic interpretation of meta-analyses, 13 and large promotion budgets.

The antidepressant market globally has exceeded $10bn (£7.6bn; €8.5bn) a year for several years. Fluoxetine (Prozac) reached blockbuster status, and esketamine is also predicted to reach sales over $1bn a year. Substantial sums are spent on marketing, advertising, public relations, and support of medical education and academia. Direct-to-consumer advertising for SSRIs has cited the monoamine hypothesis, even though it has no scientific support. 44

Money for independent reviews is negligible by comparison. The case to reduce prescribing is driven largely by patient advocates and a safety database devoid of the composites capable of summarising long term safety or identifying dependence. Considerable expertise is needed to select patients with more severe depression who will benefit from treatment and to determine how best to wean off patients for whom the long term risk-benefit balance is not favourable.

Teaching prescribers which drug to choose, when to prescribe it, and to which patient, needs to be expanded to include when not to prescribe and how to deprescribe. Prescribers in busy practice with limited consultation time should be cautious about starting patients on antidepressants for mild or moderate depression.

John Warren is a clinical pharmacologist whose interest in antidepressants developed during 16 years spent as an expert medical assessor at the Medicines and Healthcare Products Regulatory Agency. He represented the UK on the scientific advice working party of the European Medicines Agency, which highlighted the limitations of data used to justify new antidepressant authorisations, particularly an imbalance in the use of risk-benefit composite endpoints.

Acknowledgments

I thank S Dimmitt, R Ferner, Y Looke, J Ritter, H Stamfer, and P Feldschreiber for their help.

Competing interests: I have read and understood BMJ policy on declaration of interests and declare I am paid dividends from the medical consultancy Medicines Assessment. I am a member of the joint specialty committee for clinical pharmacology and therapeutics at the Royal College of Physicians and acted as an RCP representative at the APPG for Prescribed Drug Dependence, Westminster. I advise the Cure Parkinson’s Trust.

Provenance and peer review: Commissioned; externally peer reviewed.

• ↵ Taylor S, Annand F, Burkinshaw P, et al. Dependence and withdrawal associated with some prescribed medicines: an evidence review. Public Health England, 2019. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/829777/PHE_PMR_report.pdf
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• ↵ Huetteman E. FDA Overlooked red flags in drugmaker’s testing of new depression medicine. Kaiser Health News 2019. https://khn.org/news/fdas-approval-of-new-depression-drug-overlooked-red-flags-in-its-testing/
• ↵ FDA. Esketamine—full prescribing information. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf
• Farchione T ,
• ↵ Medicines and Healthcare Products Regulatory Authority. Public assessment report—reboxetine: a review of the benefits and risks. 2011. http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con129107.pdf
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• ↵ National Institute for Clinical Excellence. Depression: management of depression. primary and secondary care clinical practice guideline no 23. 2004. https://www.nice.org.uk/guidance/CG23 .
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• ↵ Davies J, Pauli R, Montagu L. Antidepressant withdrawal. Survey of patients’ experience by the all-party parliamentary group for prescribed drug dependence. 2018. http://prescribeddrug.org/wp-content/uploads/2018/09/APPG-PDD-Antidepressant-Withdrawal-Patient-Survey.pdf
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• ↵ Carey B, Gebeloff R. Many people taking antidepressants discover they cannot quit. New York Times 2018 Apr 7. https://www.nytimes.com/2018/04/07/health/antidepressants-withdrawal-prozac-cymbalta.html
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‘In my life antidepressants have been…’: a qualitative analysis of users’ diverse experiences with antidepressants

Kerry gibson, claire cartwright.

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Corresponding author.

Received 2015 Apr 1; Accepted 2016 May 4; Collection date 2016.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

While mental health professionals have focused on concerns about whether antidepressants work on a neurochemical level it is important to understand the meaning this medication holds in the lives of people who use it. This study explores diversity in the experience of antidepressant users.

One thousand seven hundred forty-seven New Zealand antidepressant users responded to an open-ended question about their experience of antidepressants. This was analysed using content and thematic analysis.

There was considerable diversity in participants’ responses including positive (54 %), negative (16 %) and mixed (28 %) experiences with antidepressants. Those with positive experiences saw antidepressants as a necessary treatment for a ‘disease’, a life saver, a way of meeting social obligations, dealing with difficult circumstances or a stepping stone to further help. Negative themes described antidepressants as being ineffective, having unbearable side effects, undermining emotional authenticity, masking real problems and reducing the experience of control. Mixed experience themes showed how participants weighed up the unpleasant side effects against the benefits, felt calmer but less like themselves, struggled to find the one or dosage and felt stuck with continuing on antidepressants when they wished to stop.

Conclusions

Mental health professions need to recognize that antidepressants are not a ‘one size fits all’ solution.

Keywords: Depression, Antidepressants, Patient experiences, Medication use

Antidepressants are being prescribed at high levels across the developed world [ 1 , 2 ]. In New Zealand, where this study was undertaken, an estimated one in nine adults receives prescriptions every year [ 3 ]. Professional debate has typically focused on whether antidepressants ‘work’ on a neurochemical level [ 4 , 5 ] with users being viewed as relatively passive recipients of medical decision-making [ 6 ]. However there is an important body of research recognising that people are actively involved in making meaning of their medication use and that this has implications this has for the value it has in their lives [ 7 – 10 ]. Small scale qualitative research has often highlighted negative experiences [ 11 – 14 ] or noted considerable ambivalence amongst some antidepressant users [ 15 , 16 ]. Only a very limited amount of research has attempted to understand positive experiences of antidepressants, also using small samples [ 17 ].

Research suggests a range of factors predict different experiences of antidepressants, including demographic factors, psychosocial factors, people’s belief about depression, and their relationship with their prescriber [ 18 ]. Some users react differently to the same antidepressant [ 19 ] while different antidepressants produce different effects [ 20 ]. In addition, there is likely to be some fluidity in people’s views through their ‘journey’ with antidepressants [ 21 , 22 ]. Most of the qualitative studies that inform this area also recognize that while people actively make meaning of their experiences of medication use, they do so in the context of prevailing social ideas that help to shape the way that these can be thought about [ 23 ]. Currently people make sense of their antidepressant use against a contested terrain in which antidepressants are represented as an effective strategy for treating a bio-medicalised conception of depression [ 24 ] alongside concerns over the over-prescription and misuse of this medication [ 1 , 25 ].

An understanding of users’ own experiences of antidepressant use is increasingly important in the context of growing doubts about the effectiveness of antidepressant treatment [ 5 , 26 ], concerns about side effects [ 27 ] and withdrawal effects [ 28 ]. With less certainty amongst professionals that antidepressants necessarily ‘do some good’ [ 29 ], it important to gather feedback on how users themselves experience the value or otherwise of these medications in their lives.

This article analyses the responses of a large sample of antidepressant users to an open-ended survey question on the impact that antidepressants had on participants’ lives. Our analysis aims to explore the potential diversity of experiences with antidepressants and the meanings attributed to them.

This article draws from responses to one open question in an anonymous online survey exploring the experience of adult New Zealanders prescribed antidepressants. The question asked participants to complete the phrase: “In my life antidepressants have been…” The study was approved by the University of Auckland, Human Participants Ethics Committee and participants gave informed consent for their participation.

Participants

Participants were informed of an online survey via widespread media advertising. The criteria for participation included having been prescribed antidepressants in the last five years, living in New Zealand and being 18 years of age or over. The survey was available online from March 2012 until January 2013. There were 1,829 completed surveys for analysis. The majority of the sample was women (77 %). The modal age group was 36-45 (24.2 %); 16.3 % were 18 to 25, and 15.9 % were 56 or older. Population figures suggest that 13.7 % of the New Zealand population is 65 or older [ 30 ] while only 3.6 % of our sample were over 65. The sample also appeared to have a somewhat higher education than the general population with 49.6 % reporting they had a university degree; 26.1 % gained a diploma or certificate after high school, 17.2 % completed high school, and 7.1 % did not complete high school as compared with 14.2 % of adult New Zealanders who had an undergraduate degree or higher and 22.4 percent who had no formal qualification in 2006 [ 31 ]. The annual income of this sample ranged from less than NZ$10,000 (15.0 %) to over NZ$100,000 (7.7 %). The modal income was $40,000 to $59,999 (22.1 %) as compared to the median income of the New Zealand population in 2012 which was $29,000 [ 30 ].

Nearly all participants (97 %) had taken the antidepressants when prescribed them, and 69 % were still taking antidepressants. Just over half (51.7 %) had taken them for more than three years, and 7.8 % for less than three months. Of the 1,715 (93.8 %) who answered a question about which antidepressant they had been prescribed, the most common was Fluoxetine (22.4 %), followed by Citalopram (20.3 %), Paroxetine (8.7 %), Tricyclics (4.5 %) and Venlafaxine (2.2 %). Thirty nine percent reported that they had been prescribed multiple antidepressants.

The question analysed in this article was only completed by those who reported that they had actually taken antidepressants following a prescription (1747 participants or 97 % of the total survey sample of 1829).

Data analysis

Participants’ responses, ranged from one word answers through to about 400 words. In order to analyse this large number of responses an initial content analysis was used to generate a quantitative description of the data and provide an overarching framework for a more detailed analysis [ 32 ]. Three pre-determined categories were used to code each participant’s response as a whole: ‘positive’, ‘negative’ and ‘mixed’ as well as a separate category for those who did not answer the question as it was intended. The coding was performed by the first author. Ten percent of responses were blind coded by the second author to check for consistency and areas of ambiguity or difference were addressed in the final coding. As there was high agreement in the initial cross-coding, further checks were not required.

Thematic analytic methods were used to identify themes within each of the three content categories. Braun & Clarke’s method provided the framework for this analysis, which involved initially identifying and coding key ideas [ 33 ]. This process was continued until the point of saturation [ 34 ]. Codes were then linked together into themes that reflected a shared meaning.

The content analysis showed that 54 % (939) of participants gave a positive account of antidepressants in their lives. Sixteen percent (273) of participants reported predominantly negative experiences and 28 % (489) described ‘mixed’ experiences. Two percent of responses did not fall into any of these categories (e.g. an elaboration of symptoms of depression).

Positive experiences of antidepressants

In keeping with neurochemical explanations of depression many participants described antidepressants as a necessary treatment for a ‘mental illness’ often referring to the ‘serotonin deficiency hypothesis’ which sees depression as a result of a chemical imbalance, as the following participant explained: [Its] just like diabetes – a chemical shortage…I need serotonin uptake inhibitors – simple!” These participants saw antidepressants as a necessary and ongoing treatment for an underlying disease: “I would hope that one day I could stop taking them but realize that for me it is the same as taking heart pill for someone else.”

This illness framework sometimes involved resignation that the participant needed to remain on antidepressants indefinitely, as one participant explained: “My GP said that if I had diabetes I would need to take insulin forever, so not to worry that I appear to need to continue to take anti-depressants forever.”

While some participants described antidepressants as a rational treatment for a disease, other responses conveyed a stronger emotional investment in antidepressant use. A number simply described them as ‘a life-saver’ conveying a sense of the distress which had led them to take antidepressants and the relief they experienced once on antidepressants: “I can still remember the desperation and pain and if it meant taking them forever I would not hesitate.” A number of people elaborated the idea of antidepressants as a life-saver in more literal form, implying that medication had prevented them from committing suicide. As one participant put it, ‘I truly feel that I would not be alive if I had not taken them”.

A third theme within the positive responses characterized antidepressant use as enabling ‘normal’ social functioning. [Antidepressants are] the sole reason I can now function as normally as possible as a human being and a participating member of my family and community.” Part of this seemed to be that antidepressants allowed them to better fulfill the demands of their social roles. As one participant put it: “[they have been] very helpful, they have allowed me to be a better parent than I would have otherwise been, I believe.”

A fourth theme was somewhat different, describing antidepressants as a temporary way of dealing with challenging circumstances – including interpersonal and social problems. Participants alluded to a range of difficult circumstances as the following response suggestions: “[Antidepressants are] helpful in enabling me to manage the stresses of job loss and unemployment. I feel that I can cope better with job interviews on them.”

In some cases, antidepressants were seen not so much as a solution on their own but as a ‘stepping stone’ to some other kind of strategy or support as the following response suggests:

I have had such good therapy that I have been able to address the wider issues that had contributed to my mental state. …Without the medication though, I would never have had the ability to do this.

For participants who understood antidepressants this way, the medication was generally seen as a temporary solution with therapy providing the more lasting benefit.

Negative experiences of antidepressants

For a number of participants negative experiences of antidepressants were underpinned by a belief that antidepressants were simply ineffective: “They were a waste of time and did not help me”. Some actively contested the idea that medication could be more helpful than other self-directed strategies of coping: “I get more benefit from mild to moderate exercise, or energy drinks, or spending quality time with friends.” Other participants wrote that they had initially had expectations that antidepressants would help them and had become increasingly disillusioned with their experience, as the following participant describes: “[They were] greatly disappointing. I wish I had never tried them, because before I tried them at least there was hope that something could have helped.”

The unpleasant side effects of antidepressants formed a second dominant theme in the negative category of responses with a number of participants explaining that they had struggled with the various side effects of different medicines over what appeared to be a lengthy period of time:

Each one has had a worse effect than the previous…. I can’t remember them all. It started with memory loss then progressed to me becoming borderline catatonic staring at the wall for hours unable to stand up. Within a few weeks and genuinely terrified. It was a relief to go back to the misery of depression after these experiences.

For some participants the journey to find an antidepressant that did not produce adverse effects had become the primary focus of their lives: “[It’s been] a never ending struggle to find the right ones that do not produce adverse health problems.”

Another of the prevalent theme amongst the negative experience responses related to concerns with emotional numbing and the loss of emotional authenticity. A number of participants wrote of feeling “like a zombie.” One participant elaborated on how he understood antidepressants to ‘work’: “They don’t make the problems go away. They just make me numb enough to not give a shit.” Another explained how the emotional numbness impacted on her life more generally: “By taking the medication I felt alienated from others almost as though I was walking around like a zombie in a kind of bubble.”

A related theme suggested that antidepressant use was felt to invalidate the genuine suffering participants had experienced. As the following participant put it: “In my life antidepressants have been prescribed to me to cover up what was wrong, and to me were a fake fix.” Some people also wrote about how antidepressants had led them to tolerate circumstances which they would have done better to address directly: “I believe that I stayed in a relationship that was unhealthy for me, because the antidepressants made me tolerate treatment that was unacceptable.”

A final negative theme captured the way that participants felt that antidepressants had undermined their control over their lives. For some taking antidepressants seemed to raise fears of personal weakness. For example, several participants wrote about using antidepressants as a sign of failing to “cope” or as a sign of dependency:

[It’s] like smoking. When you smoke you know it’s bad for you, but you also feel momentary relief and therefore can’t (or don’t want to stop) because you miss that feeling of being slightly more capable to handle situations.

A small number of participants linked their lack of control while on antidepressants to the lack of power over treatment options they experienced in relation to their treatment more generally:

I felt bullied into keeping taking them and at times told I would not receive therapeutic treatment if I didn’t take them. There felt like no alternative and I felt very trapped into taking them.

Mixed experiences of antidepressants

Many participants wrote about how using antidepressants entailed a constant struggle to balance perceived benefits of the medication with side effects. For example, one participant described antidepressants as “a necessary evil, with very unfortunate side effects in terms of weight gain and sexual dysfunction which lead to me stopping the treatment despite its benefits for my mood.” Participants wrote particularly about sexual side effects and how they had to weigh up the negative impact of antidepressants on their intimate relationships with the benefits they felt antidepressants provided to these same relationships. While some, like the previous participant, had ended up stopping antidepressants because of side effects, others resigned themselves to living with these:

I know they do me good and I am better on them, but they do make me feel physically sick, and not like myself. I seem to be constantly trying life without them, but always go back to them in the end.

A second theme illustrated how participants felt grateful that antidepressants took the edge off their distress but also struggled with a sense that they did not feel ‘like themselves’:

Antidepressants have been a two edged sword. I felt less affected by things that would normally distress me while on anti-depressants… [but] when I came off them, my head felt clear, I felt like I was waking up and that I was in touch with myself again.

Another participant reflected on a similar dilemma in which she appeared to weigh up the benefits in terms of reduced feelings of depression and changes in the way she related to others:

[Antidepressants were] helpful in making my depression less. However, the effects that they had on me as a person and how I treated others is the main reason I came off them. I am a considerate and selfless person and while on the antidepressants I was the complete opposite.

A third mixed theme showed how participants actively balanced the concerns about being ‘dependent’ on them with their fears about their depression returning if they stopped taking the medication. One participant explained how she become so used to being on antidepressants and was afraid of how things would be without them:

The thing is that I have been on them so long that I have no idea what it would be like not to be on them. I would love to come off them but they have become such a ‘normal’ part of my life since I was approximately 15 years old that I am not sure I would cope without them.

Some participants implied that there had been little follow-up or advice on how to come off antidepressants as one participant wrote:

They helped me get back on my feet when I was facing a difficult time. However I was never told when to go off them and …have not heard from the doctor who prescribed them to me in years.

Participants also described how withdrawal effects made it especially difficult to come of the medication:

The withdrawal effects if I forget to take my pill are severe shakes, suicidal thoughts, a feeling of too much caffeine in my brain, electric shocks, hallucinations, insane mood swings. [I’m] kinda stuck on them now coz I’m too scared to come off it.

In contrast to responses which emphasized balancing concerns and perceived benefits of antidepressants, some attributed their mixed experience of antidepressants to the variable effects of the different medications they had been prescribed while for others they felt there had been changes in their own response to a single antidepressant over time. A few participants described how antidepressants appeared to have been initially effective but became less so over time in spite of increased dosages, and for others their response varied markedly with the different medications they had tried:

I have been on MANY different antidepressants. None of them were helpful at all to me until I tried Fluoxetine 4 years ago. My life now is greatly improved by taking this medication and a quality of life has returned.

The responses of many of these participants seemed to capture the struggle of taking different medications over time and struggling to find the one that worked for them:

I have tried almost all antidepressants available under prescription (including combinations), and most worked to varying amounts to start with, then stopped helping, then the dose was increased, then stopped working/made me worse, then dose increased to the maximum, then stopped working, then I was put on something else. I’ve wondered if I would have been better off never starting taking them at all (see Table  1 here).

Content categories and themes

Content category: Other 2 % ( n 46)

This research points to the inadequacy of asking the simple question: ‘Do antidepressants work?’ Instead, the value or otherwise of antidepressants needs to be understood in the context of the diversity of experience and the particular meaning they hold in people’s lives. Our research suggests that meanings underpinning positive experiences of antidepressants are much less homogeneous than we might have anticipated.

In spite of limited scientific support for the idea that antidepressants correct a chemical imbalance, participants have clearly been influenced by myths about ‘serotonin deficiency’ which are widely promoted to the general public [ 35 ]. However there were a range of other meanings attributed to antidepressant use which went well beyond bio-medical considerations. Some participants saw them as having both real and metaphorical life-saving properties while other suggested more temporary and pragmatic uses in relation to meeting social obligations, dealing with difficult circumstances or as a stepping stone to other forms of help. The diversity of meaning suggests that users may be appropriating the medication in different ways according to their own priorities and concerns.

This research also suggests that a large number of people may be to some extent dissatisfied with their antidepressant use. The number of participants who reported some degree of negative experience constitutes a significant proportion (44 %) of the overall sample. Some experienced little benefit from antidepressants while the side effects, particularly more subtle psychological effects such as feeling numb or ‘not like themselves,’ seemed a significant issue, which was also found to affect many participants in the analysis of the general survey data [ 36 ]. The research also raised concerns that, in some cases, managing the side effects of antidepressants might take priority over managing the depression or circumstances that helped to produce it. Participants were also concerned about the medication undermining the legitimacy of their suffering and undermining their sense of control.

Overall, the purely negative responses were far fewer than the ambivalent responses which point to the struggle that a significant proportion of people may experience in choosing to use antidepressants. The search for the right antidepressant at the right dosage may be a long and frustrating journey for some. Experimentation with dosage may also by risky insofar as research suggests that higher dosages do not necessarily produce increased efficacy but may result in greater problems with withdrawal [ 37 ]. For users, staying on antidepressants may involve an on-going negotiation between perceived benefits and the problems they are seen to cause. This research also raises concerns about whether people remain on antidepressants despite their misgivings because of fears that they would not be able to cope without medication, withdrawal effects and lack of support from their mental health providers to manage this process.

It is important for mental health professionals to recognize that antidepressants are not a ‘one size fits all’ solution. They need to enter into dialogue with antidepressant users to explore the meaning antidepressants hold in their lives and the extent to which these enable or constrain their ability to make informed choices about their use. In making decisions about whether to take antidepressants, users should not be given misleading information about a known chemical aetiology in depression. They should instead be fully informed about the existing research on the efficacy of antidepressants relative to or in combination with psychosocial treatments [ 38 ]. In addition they might be usefully referred to research on user’s experiences [ 18 ] as well as receive full information about common side effects [ 27 , 36 ] and withdrawal effects [ 28 ] so that they can make informed treatment choices.

The findings of this study should be interpreted in the context of its limitations. The volunteer sample might well favor responses from people who have a stronger investment in the issue, such as those who had been on antidepressants for longer. Certainly, more than half the participants in this study had been on antidepressants for more than 3 years. A volunteer sample is also likely to attract those with stronger views about antidepressants. In this study, 84 % of participants in this study answered in the affirmative to a question about whether they felt antidepressants had reduced their depression, a number well above that suggested by efficacy studies [ 5 , 26 ]. This suggests that the findings of this study might over-represent positive responses to antidepressants. In addition the format of internet survey might have restricted the extent to which participants felt able to elaborate more complex or ambivalent responses.

Using an internet survey might also have skewed the sample towards a more educated and financially well-resourced group of participants and favoured a more youthful sample. The overrepresentation of women (76.6 %) is a less significant bias as they are prescribed antidepressants at much higher rates than men [ 39 ]. Concerns have been raised about limited access of potential participants to the internet but it has been recognised that this is changing quickly over time and varies considerably from one country to another [ 40 ]. In New Zealand, 80 % of households are reported to have access to internet [ 41 ].

Ethics approval and consent to participate

This study was approved by the University of Auckland Human Participants Committee Reference Number 7340. Potential participants were directed to an online information sheet which provided details about the project including its purpose, safeguards for their anonymity and the uses to which the data would be put. They were asked to demonstrate their consent to participate by then clicking through to the survey.

Consent for publication

Not applicable.

Availability of data and materials

Aggregated survey data can be requested directly from the authors.

This research was funded by the University of Auckland Faculty Research Development Fund. The funding body had no control over the design, collection of data, analysis or writing up of the research.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

KG participated in the design of the study, data collection processes, conducted the qualitative analysis of the data required for this paper and prepared the draft of the paper. CC and JR participated in the design of the study, data collection processes, and provided comment on the draft of the paper. CC cross-coded a portion of the data. All authors read and approved the final manuscript.

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Choosing an antidepressant

Philip boyce, cassandra ma.

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Issue date 2021 Feb.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.

A biopsychosocial and lifestyle approach should be used when managing depression. Many patients seen in primary care do not require drug therapy

Evidence-based treatments such as psychological therapies and antidepressant drugs are effective for depression. All patients should receive education about depression

Shared decision making with the patient is critical if an antidepressant is prescribed. The choice of antidepressant depends on its efficacy and tolerability, the depressive presentation, patient preference and drug interactions

Keywords: depression, selective serotonin reuptake inhibitors, tricyclic antidepressants

Introduction

Major depression is best conceptualised using a biopsychosocial and lifestyle model. 1 All those factors need to be considered when formulating a management plan. Lifestyle factors (such as alcohol or substance misuse, lack of exercise or poor sleep habits) that may be contributing to the onset and maintenance of the depressive episode need to be dealt with concurrently (see Table 1 ). There is a need to be mindful of any psychosocial factors, such as unemployment or interpersonal stress, that maintain the depression.

Table 1. Lifestyle factors and interventions for depression.

All patients should receive psychoeducation with a discussion about the symptoms of depression, contributing factors and management options. When appropriate this education can involve other people close to the patient.

Specific treatments

While attending to lifestyle factors and providing psychoeducation may be helpful for some patients, others need more specific treatments. These are formulation-based psychological treatment and antidepressant drugs. The efficacy of psychological treatment, such as cognitive behavioural therapy, is equivalent to drug therapy in mild–moderate disease. Ideally, psychological treatment should be offered first, unless the patient refuses or is unable to access or afford psychological treatment, or expresses a strong preference for drug treatment. Sometimes there is a clear indication for prescribing an antidepressant drug.

Indications for drug therapy

Antidepressant drugs are indicated for patients with:

major depression (characterised by marked symptoms and functional impairment)

melancholia (characterised by significant psychomotor symptoms – agitation or retardation)

psychotic depression (depression with delusions or hallucinations).

Antidepressants are also indicated for patients who have had a previous good response to them and for when psychological therapies are not accessible or have been ineffective. Even if a drug is indicated, psychoeducation along with basic counselling is still required.

Drug selection

The choice of antidepressant for a particular patient should be based on four major considerations:

finding the right balance between efficacy and tolerability

matching the antidepressant to the type of depression and its presenting features

safety – risk of overdose, interactions with other drugs or medical disorders (some groups need special consideration, such as older patients and women during pregnancy and lactation, as the baby will be exposed to the antidepressant) 2

patient preference.

There is not yet sufficient evidence confirming that the choice of antidepressant should routinely be made using pharmacogenetic data. Patients, particularly those vulnerable to marketing messages, can be advised that, except in some very special cases, genetic testing is not essential. They can save money by not paying for genetic tests.

Balancing efficacy with tolerability

The efficacy of antidepressant drugs has been confirmed in a network meta-analysis. 3 Each antidepressant was compared with other antidepressants using data from randomised placebo-controlled trials. ‘Dual-acting’ antidepressants that target more than one neurotransmitter system, such as the serotonin noradrenaline reuptake inhibitors (SNRIs) and tricyclics, are more efficacious than ‘single-action’ drugs, such as the selective serotonin reuptake inhibitors (SSRIs) like sertraline and escitalopram, based on the odds ratio of achieving a 50% response (see Table 2 ). 3 This meta-analysis also examined the acceptability of the various antidepressants by comparing the drop-out rates in clinical trials. While this is a useful metric of acceptability, the rates of adverse effects for each antidepressant are more useful in clinical practice.

Table 2. Efficacy of antidepressants compared to placebo.

Table 3 summarises the common adverse effects ranked according to a ‘limitation’ score for each of the antidepressant classes. The frequency of adverse effects can vary greatly between antidepressant classes, due to having different mechanisms of action. There are fewer differences between drugs in the same antidepressant class, although there are some exceptions.

Table 3. Antidepressant adverse effects and their limitations on use.

• Minimal limitation

•• Some limitation

••• Marked limitation

† There is little variation in the severity of adverse effects within classes of antidepressants (but patients may differ in the adverse effects they experience). One exception is the withdrawal symptoms following discontinuation of SSRIs. There is an absence of withdrawal symptoms for fluoxetine but very severe withdrawal symptoms for paroxetine.

In general, for an uncomplicated mild–moderate depression, the first choice of antidepressant should be a drug that will be well tolerated and has good efficacy. The ease of switching treatment 4 should be considered because the first antidepressant may not lead to full remission, requiring the patient to change to a different antidepressant. 5

For patients with a severe depression or melancholia (characterised by significant psychomotor change), the prime consideration is efficacy rather than tolerability. The first choice will then be one of the more potent antidepressants, generally a dual mode-of-action drug, such as an SNRI or a tricyclic antidepressant.

Matching the antidepressant to the clinical presentation

Antidepressants differ in the specific symptoms that they target, so it is possible to choose an antidepressant according to the patient’s clinical presentation. It is also possible to use the adverse effects to target specific symptoms. For example, mirtazapine is sedating, so it is an option for patients with significant insomnia. Mirtazapine is also associated with weight gain so it may be useful for major depression accompanied by significant weight loss. 6 In short-term trials, the serotonin modulator vortioxetine benefited patients who had major depression with marked cognitive deficits. 7

The choice of an antidepressant also depends, to some degree, on the symptom profile of the patient or a specific subtype of depression. 8 Table 4 lists the antidepressants that are preferred for different depressive symptom profiles. Many patients with major depression in primary care also have significant symptoms of anxiety or have a comorbid anxiety disorder. The antidepressant of choice here is an SSRI. 9 For patients with a melancholic depression, which has a clear biological underpinning characterised by vegetative symptoms and psychomotor change such as agitation or retardation, a dual-action antidepressant should be the first option. The tricyclic antidepressants or duloxetine may be used in certain neuropathic pain conditions. While they can be prescribed for patients with pain and associated depression, the doses of a tricyclic used to treat major depression need to be higher than those used for adjunctive therapy in pain management.

Table 4. Symptoms and initial antidepressant choice.

Safety considerations.

Patients with depression can often have suicidal thoughts and may try to commit suicide. This needs to be considered when prescribing an antidepressant. A suicidal patient should not be given quantities of a drug that could be fatal in an overdose. The SSRIs have a much lower potential lethality than the tricyclic antidepressants.

Ask about any other drugs the patient may be taking to avoid potential interactions. For example, there is an increased risk of serotonin toxicity when taking SSRIs in combination with tramadol, St John’s wort or monoamine oxidase inhibitors (MAOIs). SSRIs are also associated with increased bleeding due to changes in platelet function. Caution is therefore needed if they are taken with anticoagulants or non-steroidal anti-inflammatory drugs (NSAIDs). With the increased risk of bleeding, there is a need to consider any comorbid conditions that may add to this risk. In order to limit potential drug and disease interactions, it is recommended that prescribers only use a few antidepressants that they know and understand well. 10

Patient preference

A key consideration is patient preference. Adherence to antidepressants is essential to ensure remission of the depression. A significant proportion of patients will stop their antidepressant. 11 Adherence is improved if the patient is involved in the decision about which treatment to take. This involves a discussion about the expected benefits of the antidepressant and its potential adverse effects. Some adverse effects, such as sedation, may be more acceptable to patients, but others such as weight gain may be less acceptable. Be aware that patients might have misinformation from the internet or through word of mouth that the adverse effects of an antidepressant are ‘dreadful and nobody should ever take it’. In such situations, it is essential to listen to the patient’s concerns and present them with clear and accurate information about the drug, including providing them with consumer fact sheets. This approach will improve adherence.

After deciding that a patient needs to take an antidepressant, the choice of drug depends on the severity and symptom pattern of the depressive episode. There has to be a balance between efficacy and tolerability, which also considers patient safety and preference.

Conflicts of interest: Philip Boyce has received consultancy and speaker fees, and educational support from Servier. He is on an advisory board and has received educational support from Lundbeck.

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