Which antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can initially worsen anxiety symptoms?

Which Antidepressants Initially Worsen Anxiety

SSRIs (selective serotonin reuptake inhibitors) as a class can initially worsen anxiety through a phenomenon called "behavioral activation/agitation," which typically occurs within the first few weeks of treatment, particularly with sertraline, paroxetine, citalopram, and fluoxetine. 1

Mechanism and Clinical Presentation

SSRIs cause behavioral activation/agitation that manifests as:

• Motor or mental restlessness 1
• Insomnia and nervousness 1, 2
• Impulsiveness and talkativeness 1
• Disinhibited behavior and aggression 1
• Increased somatic anxiety symptoms 3

This effect is paradoxical—while SSRIs ultimately reduce anxiety, they can transiently increase it during the initial treatment phase. 4

Specific Medications and Risk Profiles

All SSRIs can cause initial anxiety worsening, but the evidence highlights:

• Sertraline is specifically noted for causing anxiety/agitation early in treatment 4
• Paroxetine showed increased "nervousness" as an adverse event (5.5% vs 2.5% placebo) 3
• Fluoxetine FDA labeling explicitly warns about emergence of anxiety, agitation, and panic attacks early in treatment 2
• Venlafaxine (an SNRI) can produce anxiety and tremors at higher doses due to norepinephrine reuptake inhibition 5, 6

Timeline and Prevalence

• Initial anxiety worsening occurs within the first 1-2 weeks of treatment 3, 7
• Approximately 15% of patients experience worsening anxiety symptoms during the first 2 weeks of SSRI treatment 7
• After one week, patients on SSRIs show increased somatic anxiety (9.3% vs 6.7% placebo) 3
• Most adverse effects, including anxiety, emerge within the first few weeks and typically resolve 1

High-Risk Populations

Behavioral activation/agitation is more common in:

• Younger children compared to adolescents 1
• Patients with pre-existing anxiety disorders (compared to those with depressive disorders) 1
• Patients receiving rapid dose escalation or high initial doses 1, 4
• When SSRIs are combined with CYP450 inhibitors that slow SSRI metabolism 1

Prevention and Management Strategy

Start low and go slow to minimize initial anxiety worsening:

1. Initiate with a subtherapeutic "test" dose to assess tolerability 4, 8
2. Increase doses slowly at 1-2 week intervals for shorter half-life SSRIs like sertraline, citalopram, and escitalopram 4, 8
3. Monitor intensively during the first 24-48 hours after each dose adjustment 8
4. Educate patients and families before starting treatment that transient anxiety worsening may occur but does not predict treatment failure 1, 4

Critical Clinical Pitfalls

Do not confuse behavioral activation with treatment failure. Early anxiety worsening does not predict poor antidepressant response in most patients 3, 7. However, in patients with clinically meaningful baseline anxiety, worsening anxiety during the first 2 weeks may be associated with worse depressive outcomes by 8 weeks. 7

Distinguish behavioral activation from mania/hypomania:

• Behavioral activation occurs early (first month) or with dose increases and resolves quickly with dose reduction 1
• Mania/hypomania may appear later and persists despite SSRI discontinuation, requiring active pharmacological intervention 1

Monitoring Requirements

The FDA mandates close monitoring for emergence of:

• Anxiety, agitation, and panic attacks 2, 5
• Irritability, hostility, and aggressiveness 2
• Akathisia (psychomotor restlessness) 2, 5

Monitor especially closely:

• During the first months of treatment 1
• Following dosage adjustments (up or down) 1, 2
• On a day-to-day basis since changes may be abrupt 2

Reassurance for Clinical Practice

Despite initial anxiety worsening, the anxiety-reducing effect of SSRIs is notable already during the first week of treatment for most patients, with psychic anxiety improving even as somatic anxiety may transiently increase. 3 Clinically significant improvement typically occurs by week 6, with maximal improvement by week 12 or later. 1, 4