Everything You Need To Know About SSRIs
by Dr. Carlo Carandang, MD
What Is An SSRI?
SSRIs (selective serotonin reuptake inhibitors) were introduced to the world with Prozac (fluoxetine) being marketed in 1987 to treat people with depression. Other SSRIs include Paxil (paroxetine), Zoloft (sertraline), Celexa (citalopram), Luvox (fluvoxamine), and Lexapro (escitalopram). SSRIs are a class of antidepressant medications, and are also prescribed to treat anxiety disorders.
SSRIs are indicated for major depressive disorder and the major anxiety disorders, such as generalized anxiety disorder (GAD), social phobia (social anxiety disorder), panic disorder, post traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD) (the exception is for specific phobia).1 The anxiety-reducing (and depression-reducing) effect of SSRIs can become evident in the first 2 to 4 weeks of treatment, but can take up to 6 to 8 weeks until the anxiety and depressive symptoms are treated.2 Generally, when the SSRI helps to address the depressive and anxiety symptoms, then the SSRI is continued for another 12 to 24 months. If the person is still symptom-free by the end of 12 to 24 months, then the SSRI can be slowly tapered and eventually discontinued.2
How do SSRI’s Work?
SSRIs (selective serotonin reuptake inhibitors) were introduced to the world with Prozac (fluoxetine) being marketed in 1987 to treat people with depression. Other SSRIs include Paxil (paroxetine), Zoloft (sertraline), Celexa (citalopram), Luvox (fluvoxamine), and Lexapro (escitalopram). SSRIs are a class of antidepressant medications, and are also prescribed to treat anxiety disorders.
SSRIs are indicated for major depressive disorder and the major anxiety disorders, such as generalized anxiety disorder (GAD), social phobia (social anxiety disorder), panic disorder, post traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD) (the exception is for specific phobia).1 The anxiety-reducing (and depression-reducing) effect of SSRIs can become evident in the first 2 to 4 weeks of treatment, but can take up to 6 to 8 weeks until the anxiety and depressive symptoms are treated.2 Generally, when the SSRI helps to address the depressive and anxiety symptoms, then the SSRI is continued for another 9 to 12 months. If the person is still symptom-free by the end 9 to 12 months, then the SSRI can be slowly tapered and eventually discontinued.
Response Rate = 75%
SSRIs work by penetrating your brain, and it increases the serotonin neurotransmitter in the synapse, which is the space between connecting neurons. Anxiety is mediated by anxiety circuits in the brain, and these circuits are made up of neurons which connect to one another to transmit the neuronal signal within the circuit. When you look at the connection between neurons, there is a presynaptic neuron (located before the synapse), and a postsynaptic neuron (located after the synapse). When the presynaptic neuron receives a signal, it releases serotonin from vesicles and dumps it into the synapse. The serotonin neurotransmitter subsequently travels across the synapse and binds to the serotonin receptors located on the postsynaptic neuron. Thus, the signal is propagated onwards. To recycle the serotonin that remains in the synapse, the presynaptic neuron has a serotonin reuptake pump, which reabsorbs the serotonin back into the presynaptic neuron.
The problem in anxiety is that there is a deficiency of serotonin in the synapse. To increase the serotonin in the synapse, the serotonin reuptake pump can be blocked by SSRIs. SSRIs bind to the serotonin reuptake pump, and stop the reabsorption of serotonin into the presynaptic neuron. This effectively increases the serotonin in the synapse, and therefore normalizes it and reduces the anxiety symptoms.
Exactly how SSRIs work downstream from the increase of serotonin in the synapse is unknown, but we do know that it affects anxiety in the following ways:
- It dramatically reduces the symptoms of anxiety (75% response rate).2
- Antidepressants increase the production of neurons in the hippocampus and may be linked to their antianxiety effects.3-4
- The delay of the anxiety-reducing effect of SSRIs (2 to 6 weeks) may be related to its effect downstream from the increased binding of receptors by serotonin in the post-synaptic neuron, as the initiation and production of proteins to make more neurons may take weeks and this may explain the delay in clinical effect.
SSRIs can cause worsening anxiety and agitation when they are first started, so it is highly advisable to start SSRIs at the lowest dose possible and to increase it slowly. Doctors may even prescribe a benzodiazepine (temporarily) along with the SSRI to prevent any worsening anxiety that often occurs with the initiation of SSRI treatment.
Dose ranges of the SSRIs are as follows:
- Fluoxetine (Prozac) 10-40mg daily
- Sertraline (Zoloft) 25-200mg daily
- Paroxetine (Paxil) 10-40mg daily
- Fluvoxamine (Luvox) 100-300mg daily
- Citalopram (Celexa) 10-40mg daily
- Escitalopram (Lexapro) 5-20mg daily
- “Chapter 12 – Pharmacotherapy for Anxiety Disorders.” Anxiety Protocol. Carandang C. 2014. Healthy Mind Research Corporation.
- World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision. Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ; WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disoders, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J. World J Biol Psychiatry. 2008;9(4):248-312.
- Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Guilloux JP, Mendez-David I, Pehrson A, Guiard BP, Repérant C, Orvoën S, Gardier AM, Hen R, Ebert B, Miller S, Sanchez C, David DJ. Neuropharmacology. 2013 Oct;73:147-59.
- Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, Spitzer G, Santarelli L, Scharf B, Hen R, Rosoklija G, Sackeim HA, Dwork AJ. J Neurosci. 2007 May 2;27(18):4894-901.
SSRI side effects
SSRIs are systemic medications that affect the entire body. Although SSRIs are an improvement over TCAs and MAOIs with regards to side effects and tolerability, there are still numerous side effects that can occur during treatment.1-6 Up to 86% of patients who take an SSRI have at least one side effect, and the majority reported the side effects lasted beyond the initial 2 weeks of treatment.7-8 The side effects are mainly mild to moderate and reversible. However some side effects can be severe and/or long term.
Dry Mouth
Rash
Hives
Also known as urticaria.
Swelling of the skin
Inflammation can occur in the face, throat, tongue, lips, eyes, hands, feet, ankles, and lower legs.
Excessive sweating
Bleeding & bruising
Runny nose
Pain, burning, numbness, or tingling in the hands or feet
Sore teeth/gums
Peeling/blistering of skin
Respiratory symptoms
Difficulty breathing; shortness of breath.
Fever
Hoarseness
Bladder problems
Difficult, frequent, or painful urination
Sexual side effects
SSRIs can cause reduced sexual desire and anorgasmia (or delayed orgasms).
Abnormal menses (women)
Heavy menstrual periods; painful, irregular menstruation.
Vaginal problems
Swelling, itching, burning, or infection in the vagina.
Penile problems
Painful erection lasting for hours.
Weakness
Tremors
Uncontrollable shaking.
Muscle pain
Also known as myalgia.
Joint pain
Also known as arthralgia.
Stiff or twitching muscles
Joint tenderness, swelling
Numbness, tingling in the hands, feet, arms, or legs
Yawning
Dizziness
Drowsiness
Auditory/visual hallucinations
Confusion
Coma/loss of consciousness
Loss of coordination
Headaches
Seizures
Unusual excitement
Anxiety
Memory problems
Change in taste
Bizarre dreams
Nausea
Diarrhea
Constipation
Vomiting
Gas/bloating
Loss of appetite
Stomach pain
Black, tarry stools
Red blood in stools
Bloody vomit
Vomit that looks like coffee grounds
Heartburn
Weight loss
Lump in the throat
Rapid, slow, and/or irregular heartbeat
Unsteadiness
Fainting
Flushing
Chest pain
Coordination problems
- “Citalopram.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Escitalopram.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Fluoxetine.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Fluvoxamine.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Paroxetine.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Sertraline.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. Hu XH, Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, Markson LE. J Clin Psychiatry. 2004 Jul;65(7):959-65.
- Real-World Data on SSRI Antidepressant Side Effects. Cascade E, Kalali AH, Kennedy SH. Psychiatry (Edgmont). 2009 Feb;6(2):16-8.
Sexual Side Effects and SSRIs
SSRIs are commonly associated with sexual side effects, and is a common reason for discontinuing SSRIs.1 The side effects caused by SSRIs include decreased libido or sexual desire, erectile dysfunction, arousal problems, delayed or suppressed ejaculation, orgasm problems, and painful intercourse (dyspareunia). And the problem with sexual side effects may not end when discontinuing an SSRI. In fact, 12.6% of people who previously took an SSRI and discontinued it still had persistent sexual side effect.2 There is even a term for it- Post SSRI Sexual Dysfunction (PSSD). Therefore, it is important to discuss with your doctor the potential problems with sexual side effects both during and after discontinuing an SSRI.
- Antidepressants and sexual dysfunction: mechanisms and clinical implications. Clayton AH, Croft HA, Handiwala L. Postgrad Med. 2014 Mar;126(2):91-9. doi: 10.3810/pgm.2014.03.2744.
- Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship. Ben-Sheetrit J, Aizenberg D, Csoka AB, Weizman A, Hermesh H. J Clin Psychopharmacol. 2015 Jun;35(3):273-8.
Discontinuation Syndrome and SSRIs
SSRIs are associated with significant withdrawal symptoms when they are discontinued, and the symptoms can last for a few weeks (or longer). Restarting the SSRI leads to resolution within 48 hours.1 SSRI discontinuation syndrome is characterized by both physical symptoms (dizziness, shock-like sensations, ‘pins and needles’ sensation, headache, nausea, diarrhea, fatigue, tremor, and visual problems) and psychological symptoms (irritability, anxiety, and sleep problems).2 Paroxetine is associated with the worst withdrawal symptoms of all the SSRIs, and may be associated with its very short half-life.3 Even if longer acting SSRIs such as fluoxetine were substituted, it may just delay the eventual occurrence of withdrawal symptoms, and using benzodiazepines to alleviate withdrawal symptoms is not well studied. It is proposed by some researchers that SSRIs be added to the list of drugs that cause withdrawal symptoms, such as benzodiazepines and other drugs of abuse.3
- The SSRI discontinuation syndrome. Haddad P. J Psychopharmacol. 1998;12(3):305-13.
- Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. Black K, Shea C, Dursun S, Kutcher S. J Psychiatry Neurosci. 2000 May;25(3):255-61.
- Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Psychother Psychosom. 2015 Feb 21;84(2):72-81.
Suicide and SSRIs
There is a well-established increased risk of suicide in children and adults (under the age of 25) taking an SSRI, when compared to placebo.1 This led to the FDA Black Box Warnings in the mid-2000’s about the dangers of antidepressants in children and young adults, and the risk for suicide when taking these antidepressants, such as SSRIs. For adults age 25 to 64, there was no increase in suicide risk (risk was neutral) when taking an SSRI, while in adults aged 65 and older, there was a decreased suicide risk.2 Use caution with SSRIs if you are under the age of 25, given the increased suicide risk. For a more detailed discussion on suicide and SSRIs, please click here.
- Relationship between psychotropic drugs and pediatric suicidality: review and evaluation of clinical data. Silver Spring, MD: Food and Drug Administration. Hamad T (2004). (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf).
- Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, Hammad TA, Temple R, Rochester G. BMJ. 2009 Aug 11;339:b2880.
Violence and SSRIs
There has been controversy surrounding the association of violence with SSRIs. This has been highlighted by conflicting studies. One group of researchers studied serious adverse effects of drugs in the U.S. from 2004 to 2009, and found that antidepressants with effects on serotonin was associated with an increased risk of violence.1 Another group from the Netherlands looked at Dutch data from 1994 to 2008, and found that with an increase in antidepressant exposure, the rate of lethal violence decreased.2 For a more detailed discussion on the association of violence and SSRIs, please click here..
- Prescription drugs associated with reports of violence towards others. Moore TJ, Glenmullen J, Furberg CD. PLoS One. 2010 Dec 15;5(12):e15337.
- Antidepressants and lethal violence in the Netherlands 1994-2008.
Bouvy PF, Liem M. Psychopharmacology (Berl). 2012 Aug;222(3):499-506.
History of SSRIs
The SSRIs made its debut in 1986 in Belgium with fluoxetine, manufactured as Prozac by Eli Lilly. It was introduced in the United States in 1987. The SSRIs became instantly popular, as they had less side effects and were more tolerable than the antidepressants present at the time, the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs). Other SSRIs were eventually manufactured and marketed in the United States, and fluoxetine was followed by the introduction of sertraline (Zoloft) in 1991, paroxetine (Paxil) in 1992, fluvoxamine (Luvox) in 1994, citalopram (Celexa) in 1998, and escitalopram (Lexapro) in 2002. All of the SSRIs in the United States have expired patents, and are therefore available as cheaper generics.
Presentation of bias
As a psychiatrist who has to inform and educate patients of their options for treatment, it is important for an author to present his or her bias. We are human, so we will have bias, and it is impossible to be completely objective. Thus, it is important to clarify the author’s bias when reading and absorbing content.
My bias: I suffered from anxiety starting in adolescence into adulthood. I took SSRIs in my 20’s, but I could not tolerate the side effects, so I decided to look for natural, self-reliant ways to combat my anxiety. When I eventually became a psychiatrist, I found techniques that helped my patients with anxiety, and then began to apply those same techniques to help for my own anxiety. I am now able to control my anxiety symptoms with The Anxiety Protocol. Also, instead of taking prescription medications with multiple side effects, I use KalmPro, a natural anxiety supplement I formulated from research studies, to help quell my anxiety symptoms. Taking KalmPro augments the techniques I use in The Anxiety Protocol.
Dr. Carlo Carandang MD, Anxietyboss.com founder.
photo credit: Photo-A-Day 2 via photopin (license)