Sertraline (Zoloft) antidepressant may not be as effective at treating depression but anxiety symptoms


One of the most common antidepressants, sertraline (Zoloft), leads to an early reduction in anxiety symptoms, commonly found in depression, several weeks before any improvement in depressive symptoms, a UCL-led clinical trial has found.

Published in The Lancet Psychiatry and funded by the National Institute for Health Research (NIHR), this is the largest-ever placebo-controlled trial of an antidepressant, which has not been funded by the pharmaceutical industry.

By involving a wide range of patients including people with mild to moderate symptoms, the researchers surveyed a much wider group of people than most previous clinical trial samples.

Sertraline did not appear to improve depressive symptoms, which include low mood, loss of pleasure and poor concentration, within six weeks. However, there was weak evidence that sertraline reduced depressive symptoms by 12 weeks.

Participants who took sertraline were twice as likely as those who took a placebo to say their mental health had improved overall.

This is an important measure of improvement, from the patient’s perspective, and can be used to gauge clinically meaningful treatment effects.

The researchers say their findings support the continued prescription of sertraline and other similar antidepressants for people experiencing depressive symptoms.

“It appears that people taking the drug are feeling less anxious, so they feel better overall, even if their depressive symptoms were less affected,” said the study’s lead author, Dr. Gemma Lewis (UCL Psychiatry).

“We hope that we have cast new light on how antidepressants work, as they may be primarily affecting anxiety symptoms such as nervousness, worry and tension, and taking longer to affect depressive symptoms.”

Sertraline is a selective serotonin reuptake inhibitor (SSRI), the most common class of antidepressants.

The study was conducted in GP surgeries and included 653 people in England, aged 18 to 74, with depressive symptoms of any severity or duration in the past two years. In all cases, there was clinical uncertainty about whether to prescribe an antidepressant.

The researchers say the participants were more representative of the people now receiving antidepressants in the UK than in previous trials.

Most studies into antidepressants were conducted many years ago in regulatory trials for new drugs, and only included people in secondary care (specialist) mental health services.

The management of depression has changed since then and antidepressants are mostly prescribed in primary care (such as GPs) to a much broader group of patients including those with milder symptoms.

Just over half (54%) of participants met a commonly used criteria for depression (from the World Health Organisation), while 46% met the criteria for generalized anxiety (including 30% who met the criteria for both conditions, 15% who had mixed anxiety and depressive disorder while 15% did not meet diagnostic criteria but still had symptoms).

The large majority of people with depression also experience anxiety symptoms, and antidepressants are the standard pharmaceutical treatment for generalized anxiety disorder.

Half of the participants were given sertraline for 12 weeks, while the other half were randomly assigned to the control group and given placebo pills for 12 weeks.

The researchers found no evidence of a clinically meaningful reduction in depressive symptoms after six weeks, which was the primary outcome of the trial (this primary outcome was chosen in line with previous studies that have gauged improvement after six or eight weeks).

There was strong evidence that sertraline reduced generalized anxiety symptoms, with continued improvement from six weeks to 12 weeks, and led to better mental health-related quality of life.

The results did not vary by severity (at start of trial) or duration of the depressive symptoms, suggesting that antidepressants may benefit a wider group of people than previously believed, including people who do not meet diagnostic criteria for depression or generalized anxiety disorder.

There was no evidence that those on sertraline were more likely to experience side effects or adverse events than those on the placebo.

The researchers say the findings could be useful to health professionals, as clinicians should be aware of which symptoms are likely to be treated by an antidepressant.

Sertraline is a selective serotonin reuptake inhibitor (SSRI), the most common class of antidepressants.

The study’s senior author, Professor Glyn Lewis, head of division at UCL Psychiatry, said: “Our study supports the current use of antidepressants and finds that sertraline is effective for the people likely to receive antidepressants in primary care. They work, just in a different way than we had expected.

“Antidepressants can be beneficial to people with depression or anxiety but any benefit has to be set against any side effects or the possibility of withdrawal symptoms.”

Dr Gemma Lewis added: “Antidepressants are one of the most commonly prescribed medications in the UK and prescription rates have risen dramatically over the last decade in high income countries. However, we are still developing our understanding of exactly how they work.”

Funding: The study was conducted at UCL Psychiatry and the Universities of Bristol, Liverpool, and York.

Anxiety disorders are the most prevalent comorbid diagnoses in patients with bipolar disorder (BD).

The lifetime prevalence of anxiety disorders is 45% when BD is present; patients with BD are 3 to 7 times more likely to meet criteria for diagnosis of an anxiety disorder than the general population.1,2 

Panic, posttraumatic stress (PTSD), and generalized anxiety disorders (GAD) are the most common (13% to 60%), followed by obsessive compulsive disorder (OCD; 10%).13 Anxiety disorders and compulsive disorders, specifically OCD, will be addressed as a group because of the similar approaches used in treatment outside of the context of BD.

For the purposes of this review, the terms anxiety and/or anxiety symptoms can be interpreted to also include obsessive and compulsive symptoms.

Comorbid anxiety symptoms have a significant impact on the treatment of BD leading to increased severity of bipolar symptoms and use of mental health services, more frequent and severe depressive episodes, non-adherence to treatment, and decreased functioning and quality of life (Table 1).46

Take Home Points

  1. Bipolar disorder (BD) with comorbid anxiety disorders is very prevalent and can lead to a higher illness burden, greater risk of residual symptoms upon resolution of the mood episode, and decreased medication adherence.
  2. There are limited clinical trials to provide evidence for medication and other treatments for comorbid BD and anxiety disorders. Mood stabilization is generally the first priority before addressing the anxiety disorder.
  3. Polypharmacy is the rule in the treatment of comorbid bipolar and anxiety disorders. Mood stabilizer monotherapy is unlikely to be effective for all symptoms. Recognition of the need for effective treatment of the anxiety disorder is paramount in improving quality of life and minimizing suicidality.
  4. Although serotonergic antidepressants, specifically selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, are first-line medication treatments for anxiety disorders, the use of antidepressants in BD may lead to destabilization of mood and a risk of manic switch, especially when used for long-term treatment. Serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants have been associated with a greater risk of manic switch than selective serotonin reuptake inhibitors and bupropion. Mood stabilizers and second-generation antipsychotics should be used as initial treatment before treatment with antidepressants. Lithium may be more protective against manic switch than other mood stabilizers. If antidepressant therapy is warranted, it should be undertaken with caution and close monitoring.

The goals of treatment for patients with comorbid anxiety and BD are remission of symptoms and a return to baseline functioning.

Anxiety commonly occurs during a depressive episode, which partly reflects the prevalence of the comorbid diagnoses of anxiety and mood disorders but does not explain anxiety symptoms occurring during euthymia.4

 Anxiety symptoms may not commonly remit with resolution of the mood episode; this leads to a progressive decrease in functioning and quality of life, even in euthymia.

Residual anxiety symptoms may be a risk factor for limited success in the treatment of mood symptoms and may be predictive of mood symptom relapse. In a recent study evaluating the effectiveness of venlafaxine versus lithium monotherapy in acute (n = 129, duration 12 weeks) and continuation (n = 55, duration 6 months) treatment of BD II depression, the investigators evaluated the impact of comorbid anxiety symptoms on depression relapse.

Venlafaxine was more effective than lithium on depressive symptoms (P < .0001), but was less likely to improve symptoms of anxiety (P < .027). The rate of manic switch was not reported in this study.

Residual anxiety symptoms, especially uncontrollable worry, were a stronger predictor of depression relapse than residual depressive symptoms. The investigators concluded that remission of anxiety symptoms in bipolar depression may be protective against depressive relapse.7

The recognition and treatment of comorbid anxiety and BD remains an understudied area. Most published literature is descriptive in nature; few clinical trials exist related to pharmacologic and behavioral treatments.8

The cases presented in this article will highlight treatment choices for medications and psychotherapy, the risk of manic switch when using antidepressants, the with anxious distress specifier, and the need for mood stabilization prior to initiation of antidepressant treatment for patients with BD and comorbid anxiety disorders.

Media Contacts:
Chris Lane – UCL
Image Source:
The image is adapted from the UCL news release.

Original Research: Open access
“The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial”. Gemma Lewis et al.
Lancet Psychiatry doi:10.1016/S2215-0366(19)30366-9.


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