Tricyclic antidepressants (discontination syndromes)

• most common features are gastrointestinal (e.g. nausea, vomiting, abdominal pain, diarrhoea) and 'flu-like symptoms, anxiety and agitation, fatigue, sleep disturbance and nightmares (1)
  
  
• occasional features are movement disorders such as akathisia and behavioural activation with hypomania (1)
  
  
• contributory factors to development of discontination symptoms appear to be abrupt withdrawal from a high dose and longer therapy
  
  
• Primary TCA discontinuation syndrome
  • Has been suggested that characteristically features may include (2):
    • General somatic symptoms
      • Lethargy
      • headache
      • Tremor
      • Sweating
      • Anorexia
    • Affective symptoms
      • Irritability
      • Anxiety/agitation
      • Low mood
      • Tearfulness
    • Gastrointestinal symptoms
      • Nausea
      • Vomiting
      • Diarrhoea
    • Sleep disturbance
      • Insomnia
      • Nightmares
      • Excessive dreaming

• Prevention
  • Tapering after successful treatment
    • Recommendations on taper length vary
      • has been suggested that antidepressants administered for 8 weeks or more should, wherever possible, be reduced over a 4-week period
      • NICE suggest that
        • normally, gradually reduce the dose over 4 weeks (this is not necessary with fluoxetine). Reduce the dose over longer periods for drugs with a shorter half-life (for example, paroxetine and venlafaxine)
          
          
    • routine tapering is probably unnecessary when antidepressants have been prescribed for less than 4 weeks, as discontinuation symptoms are unlikely to occur with such a short duration of treatment (2)
    • an abruption of an antidepressant is justified if a patient has developed serious side effects believed to be due to the antidepressant, there is a medical emergency warranting stopping the antidepressant or the antidepressant has induced mania (2)
      
      
  • Tapering and antidepressant switching
    • data imply that if tapering SSRIs and venlafaxine is beneficial in reducing discontinuation symptoms, then it needs to continue for more than 14 days for most patients.
    • a start-taper switch refers to starting the new antidepressant and simultaneously gradually tapering the previous one
      • whether an abrupt switch or start-taper switch is chosen partly depends on the likelihood of discontinuation symptoms occurring, which in turn depends on the pharmacological similarity between the two antidepressants
    • using a washout period (no antidepressant prescribed)
      • is essential when switching to and from MAOIs because of the risk of drug interactions that can lead to serotonin syndrome
      • a washout should also be considered when switching from fluoxetine to a TCA, as the long-half life of fluoxetine, plus its ability to inhibit cytochrome P450 enzymes, could result in elevation of plasma TCA levels, leading to adverse effects (2)
        
        
• management
  • treatment of discontinuation symptoms depends on
    • (i) whether or not further antidepressant medication is warranted and
    • (ii) the severity of the discontinuation symptoms
  • if further antidepressant treatment is warranted
    • then restarting the antidepressant will cause rapid resolution of the symptoms
  • if further antidepressant treatment is not clinically indicated then management depends on the severity of the discontinuation symptoms
    • majority of symptoms are mild and in these cases treatment usually requires only that the patient be reassured about their self-limiting nature
    • if symptoms are of moderate severity then can be treated symptomatically
      • e.g. insomnia may be treated with a short course of a benzodiazepine
    • if severe discontinuation symptoms then the antidepressant can be reinstated, symptoms will usually resolve within 24 h and then the antidepressant can be withdrawn more cautiously
      • always include an appropriate explanation of the symptoms to the patient and follow-up to ensure that the symptoms have resolved
    • if, when attempting to withdraw and stop an antidepressant, severe discontinuation symptoms appear either during or at the end of a taper
      • consider increasing the antidepressant dose back to the lowest dose that prevented their appearance, and then commencing a slower taper
        • some patients may require a very gradual tapers to prevent discontinuation symptoms reappearing
          

Reference:

• Drug and Therapeutics Bulletin (1999), 37 (7), 49-52
• Renoir T. Selective Serotonin Reuptake Inhibitor Antidepressant Treatment Discontinuation Syndrome: A Review of the Clinical Evidence and the Possible Mechanisms Involved. Front Pharmacol. 2013; 4: 45.
• Haddad PM, Anderson IM. Advances in Psychiatric Treatment 2007; 13: 447-457
• Haddad, PMThe SSRI discontinuation syndrome. Journal of Psychopharmacology 1998; 12: 305-313.
• Tint, A., Haddad, P. M, Anderson, I. M. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. Journal of Psychopharmacology 2007
• NICE (October 2009). Depression