Side effects of Selective Serotonin Reuptake Inhibitors.

Examples of the SSRIs are Prozac (fluoxetine), Paxil (paroxetine), Zoloft (sertraline), Luvox, Celexa (citalopram), and Lexapro (escitalopram). Effexor (venlafaxine) also shares these side effects, even though its action is on both serotonin and another brain chemical, norepinephrine.

The following are not all the side effects of these medications; they are the ones I feel are of highest priority for patients and their families to know about. There is no side effect that occurs with every person who takes a drug. For any given side effect, some people get it and others don't.

1. Antidepressant discontinuation syndrome -- otherwise known as withdrawal effects.

The dependency that these drugs cause over time is one of the major reasons to make treatment with SSRI's of as brief a duration as possible. The longer SSRI's are given, and the higher dose they are given in, the more troublesome are the side effects when they are withdrawn. They should be withdrawn with gradually decreasing doses rather than suddenly stopping them, for this reason. The most troubling side effects when they are withdrawn are psychological effects: anxiety, depression, and irritability. Some people experience a zapping sensation in their heads. For some people these side effects are so unpleasant that they have great difficulty getting off the SSRI's, and find themselves dependent upon them. The rapid withdrawal of the antidepressants in pregnant women is associated with a high rate of onset of depressive episodes. I believe that at least some of these may not have occurred had the women gotten off the antidepressants long before or had they not gotten on them in the first place.

Reference: Psychother Psychosom 2015;84:72-81


Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. Fava G.A. · Gatti A. · Belaise C. · Guidi J.· Offidani E.

Psychother Psychosom 2012;81:386–388 DOI: 10.1159/000341178 Patient Online Report of Selective Serotonin Reuptake Inhibitor-Induced Persistent Postwithdrawal Anxiety and Mood Disorders. Carlotta Belaise , Alessia Gatti , Virginie-Anne Chouinard , Guy Chouinard

2. Suicidal ideas or behavior.

The antidepressants are of course hoped to make suicide less likely, and there is some evidence that they do so. However, at the beginning of treatment, the SSRI's may increase or cause suicidal ideation or behavior. This is the subject of a “black box” warning on the drug information approved by the U.S. Food and Drug Administration. My reading of the data is that this risk is small compared to the risk of dependence described in paragraph 1 above.

Reference: Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment. A Meta-analysis of Randomized Controlled Trials

Jeffrey A. Bridge, PhD; Satish Iyengar, PhD; Cheryl B. Salary, MD; Rémy P. Barbe, MD; Boris Birmaher, MD; Harold Alan Pincus, MD; Lulu Ren, PhD; David A. Brent, MD

JAMA. 2007;297(15):1683-1696. doi:10.1001/jama.297.15.1683.

3. Akathisia. This symptom is more often caused by the antipsychotic drugs, but it can also be caused by the SSRIs. Akathisia means an unpleasant feeling of physical restlessness – the urge to keep moving. Sometimes people with akathisia pace around, or keep changing position while sitting. This goes far beyond the ordinary restlessness that people have when they've been sitting for a long time or feel bored. Reducing the dose of, or discontinuing, the SSRI almost always eliminates this side effect.

Reference: Ann Pharmacother. 2015 Oct;49(10):1136-52. doi: 10.1177/1060028015594812. Epub 2015 Jul 16.Extrapyramidal Reactions Associated with Serotonergic Antidepressants. Hawthorne JM, Caley CF.

4. Birth defects.

There is some evidence that the use of the SSRIs during pregnancy increases the risk of certain birth defects. This question is far from settled, partly because when increases in birth defects have been found, the increase in risk has been from a very small number to another still very small number. Also the increases in risk appear to vary from one drug to another. The possibility of increased risk, however, combined with the dependency upon the SSRIs that develops over years, is one reason why I am particularly reluctant to keep pre-teen and adolescent girls on the SSRI's for a long time.

(Reference: Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. BMJ 2015; 351 doi: (Published 08 July 2015) Cite this as: BMJ 2015;351:h3190)

Anderson KN, Lind JN, Simeone RM, et al. Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects. JAMA Psychiatry. 2020;77(12):1246–1255. doi:10.1001/jamapsychiatry.2020.2453

5. Serotonin syndrome.

This is very rare. This syndrome is dangerous and can be life-threatening. It is more likely when there are combinations of drugs that interact with one another – such as a monoamine oxidase inhibitor and an SSRI. However, there have been rare cases that have come from an SSRI alone. Symptoms include muscle rigidity, jerky muscle movements, shaking, loss of coordination, high fever, agitation, seizures, and getting delerious. If this occurs, the SSRI should be discontinued immediately, and usually the person should be hospitalized. A drug such as cyproheptadine that opposes serotonin can help. Benzodiazepines can help reduce agitation and jerky muscle movements.

Reference: BMJ Case Rep. 2013 Feb 20;2013. pii: bcr2012008314. doi: 10.1136/bcr-2012-008314.

Serotonin syndrome: pills, thrills and shoulder aches. Proudfoot M1, Gormley J.

6. Weight gain.

This is a long term side effect that doesn’t occur at the beginning of treatment, but seems to sometimes come on with more extended treatment times.

Reference: Innov Clin Neurosci. 2014 Nov-Dec;11(11-12):14-21. Antidepressant use and body mass index change in overweight adolescents: a historical cohort study. Cockerill RG, Biggs BK, Oesterle TS, Croarkin PE.

Lee, S. H., Paz-Filho, G., Mastronardi, C., Licinio, J., & Wong, M. L. (2016). Is increased antidepressant exposure a contributory factor to the obesity pandemic?. Translational psychiatry, 6(3), e759.

7. Sleep difficulties.

This also seems to be a side effect that sometimes occurs with extended treatment times.

Reference: Prim Care Companion J Clin Psychiatry. 2001 Feb; 3(1): 22–27.PMCID: PMC181155

SSRI Antidepressant Medications: Adverse Effects and Tolerability. James M. Ferguson, M.D.

Rahmadi M, Narita M, Yamashita A, Imai S, Kuzumaki N, Suzuki T. Sleep disturbance associated with an enhanced orexinergic system induced by chronic treatment with paroxetine and milnacipran. Synapse. 2011 Jul;65(7):652-7. doi: 10.1002/syn.20893. Epub 2011 Feb 25. PMID: 21157932.

8. Sexual difficulties.

These medications often interfere with sexual functioning and enjoyment.

Reference: Prim Care Companion J Clin Psychiatry. 2001 Feb; 3(1): 22–27.PMCID: PMC181155

SSRI Antidepressant Medications: Adverse Effects and Tolerability. James M. Ferguson, M.D.

9. Apathy

Patients sometimes report that the SSRIs tend to make it easier to think, "Well, whatever," in other words, "I don't care so much," "The stakes seem low," "It doesn't make all that much difference." Sometimes with anxiety or obsessive compulsive problems this effect is very helpful and welcomed. But cases have been reported where the effect went too far, and the patient experienced apathy and loss of motivation that was very much unwelcomed.

Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract. 2004 May;10(3):196-9. doi: 10.1097/00131746-200405000-00010. PMID: 15330228.

Side Effects of the Alpha Adrenergic drugs

Examples: clonidine and guanfacine (Catapres, Kapvay are trade names for clonidine; Tenex and Intuniv are trade names for guanfacine)

The following are not all the side effects of these medications; they are the ones I feel are of highest priority for patients and their families to know about. Any side effect occurs only in a certain fraction of people taking the drug.

1. Low blood pressure. Both of these drugs were originally marketed as treatments for high blood pressure, and they can occasionally cause problems by causing low blood pressure. The most frequent problem with low blood pressure occurs just after you stand up from sitting or lying down. When this occurs, you feel a very sudden feeling of “lightheadedness” or feel as if you are going to faint. This occurs because the blood pressure is temporarily not enough to get the blood up to the brain effectively enough. The important thing to remember is that if someone experiences this, he should immediately bend over, kneel down, or otherwise lower the head relative to the rest of the body. Bending over or kneeling down quickly can prevent a faint, and a fall that would result from it. If you find that bending over or kneeling down immediately makes the lightheaded feeling go away, you are even more sure that low blood pressure was the cause of the problem. You can then get up more gradually.

The problem of lightheadness or faintness upon standing up appears to be not very frequent in adolescents and even less frequent in younger children.

2. Low heart rate. These drugs can both make the heart beat more slowly. For this reason it's good to check the heart rate periodically when someone is on either of these drugs. For most people this causes no problem at all.

3. Sleepiness. This is more a side effect of clonidine than of guanfacine. Clonidine is often prescribed as a sleep aid, to take advantage of this side effect. But you don't want someone made sleepy by either of these drugs especially when they're driving a vehicle (even a bicycle or skateboard!) or dealing with dangerous machinery, etc.

4. Withdrawal hypertension. When the body gets used to a drug that tends to lower blood pressure, and then that drug is withdrawn, the blood pressure can go up too high. For this reason, these medications should be withdrawn slowly unless they are at a low dose. For low doses, you can almost always discontinue these medicines without a problem of rebound high blood pressure.

5. (No) effect on cardiac conduction? The extent to which a medicine increased the QTc interval or the PR interval of the EKG (electrocardiogram) is something of a measure of whether it poses a risk for dangerous heart rhythm problems. Clonidine does not appear to have an effect on either of these intervals.

Kofoed L, Tadepalli G, Oesterheld JR, Awadallah S, Shapiro R. Case series: clonidine has no systematic effects on PR or QTc intervals in children. J Am Acad Child Adolesc Psychiatry. 1999 Sep;38(9):1193-6. doi: 10.1097/00004583-199909000-00026. PMID: 10504820.

Side effects of Methylphenidate (Ritalin, Ritalin LA, Focalin, Focalin XR, Concerta, Metadate CD)

The following are not all the side effects of this medication; they are the ones I feel are of highest priority for patients and their families to know about. There is no side effect that occurs with every person who takes a drug, as a general rule; some people get the side effect and others don't. However, with methylphenidate some lowering of appetite during the time the drug is on board and some reduction of sleepiness while it's on board happen in a very high fraction of people who take it. Usually these are not big problems. Despite the side effects listed below, I believe that methylphenidate is one of the safest drugs, or perhaps the safest one, prescribed for mental health effects.

1. The “rebound effect.”

With nearly every drug that affects the brain, the drug has the opposite effects when it is wearing off than it has when the drug has its onset. Methylphenidate is meant to increase focus, patience, thinking before acting, ability to stay in one place, and emotional stability. When it wears off in the afternoon or evening, there is a withdrawal reaction in some (but not all!) children, where they go through a time where they are more impatient, more impulsive, more active, less able to focus, and more irritable. Because of the rebound effect, sometimes teachers see great benefit from the medication while parents “have the devil to pay” in the form of the rebound period. Sometimes clonidine or guanfacine is given at wearoff time to reduce these effects.

2. Legal side effects.

Methylphenidate is a controlled substance. According to my reading of New York State Law, (which I understand is similar to other states in this regard) selling or even giving away the medicine prescribed for one person to anyone else is a felony. Thus one can experience severe legal consequences for giving or selling the medicine to anyone other than the person it was prescribed for.

3. Sleep difficulties.

Fortunately methylphenidate is eliminated from the body rapidly. “Regular” methylphenidate, coming in a pill with nothing that makes the pill release the medicine slowly, lasts about 4 or 5 hours. Focalin XR, Ritalin LA, and Metadate CD last around 8 hours, and Concerta lasts about 12 hours, not because there is a longer acting drug inside, but because the methylphenidate in the capsule is arranged to release itself into the gut slowly. If by mistake you take regular methylphenidate within 3 or 4 hours of bedtime, or if you take any of the others in the afternoon or evening, you may be kept awake at night. Sometimes students are tempted to use this side effect when they want to “pull an all-nighter” working on a late assignment. Using drugs to stay awake for a long time is a very bad idea; this temptation can be considered another side effect of the medicine.

A related problem occurs when someone stays up too late at night, and becomes very sleep deprived. Ordinarily, the body takes care of sleep deprivation when the person tends to fall asleep while watching tv, riding on a bus, listening to a lecture, or whatever. But methylphenidate can keep the person awake during these times, and make the person able to get deeper and deeper into a “sleep debt” without being forced by the brain to pay off the debt. The result can be the irritability, reduced mental efficiency, and emotional lability that go along with insufficient sleep.

4. Appetite loss, and effects on growth.

Appetite usually rebounds after methylphenidate wears off at the end of the day; if a child is allowed to “make up for lost time” by eating nutritious food after the medicine wears off, this will help keep the child from not getting enough nutrition. Methylphenidate can reduce the rate of growth in children, in height as well as weight; most of this effect probably occurs when children don't eat enough. The effect of methylphenidate upon eventual height attainment has been very hard for people to measure. Children who get methylphenidate, particularly in high doses, for most or all of their growing years may be at higher risk for being a little shorter than they would otherwise have been.

It appears that usually if methylphenidate affects height or weight, the height or weight rebounds when you stop giving the medicine. Here's the way one review article put it: “Notably, all but two studies of treatment cessation suggest that discontinuation of stimulant medication is followed by a rebound in growth to compensate for medication induced losses, which results in the formerly treated children returning to their normal growth percentiles.” (Reference: Faraone SV1, Biederman J, Morley CP, Spencer TJ (2008) Effect of stimulants on height and weight: a review of the literature.

J Am Acad Child Adolesc Psychiatry. 2008 Sep;47(9):994-1009. doi: 10.1097/CHI.ObO13e31817eOea7.)

5. Effects on the heart (?)

At one time, regulators in both Canada and the United States became quite concerned about effects that methylphenidate may have upon the heart. A few children died suddenly while taking methylphenidate, presumably because of cardiac (heart) problems. However, research done after that indicated that there is a certain low rate of sudden cardiac death in children, and the rate for those on methylphenidate does not appear to exceed that in the general population. At the time of most concern, some people spoke about routinely getting EKGs before starting methylphenidate. Subsequent work on the question indicated that this is unnecessary, unless there is a family history of rhythm disturbances of the heart or a history in the child of heart disease.

A 2014 review of the cardiac safety of methylphenidate (along with two other drugs) gave this conclusion:

“Several large studies of the very rare phenomenon of sudden death in children have failed to show any convincing association with ADHD treatment.”

Reference for this article is: Awudu GA, Besag FM (2014) Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder: an update.

Drug Saf. 2014 Sep;37(9):661-76. doi: 10.1007/s40264-014-0201-8.

Methylphenidate has been found in some studies to increase blood pressure and heart rate a little bit. But the average amounts of increase are not of clinical significance. Rarely, an individual will have blood pressure increased by the drug enough that treatment has to be changed. Routine checking of blood pressures and pulse rates for those prescribed methylphenidate should be done, but it hardly ever reveals any effect worth doing anything about.

6. Tics(?)

Tics are brief twitchy movements, usually of the mouth or eyebrows or eyelids or other facial muscles. Years ago, it was thought that tics were a sufficient reason not to start methylphenidate or to discontinue it if tics developed. More recent research has called into question the entire association between drugs such as methylphenidate and tics. A 2015 meta-analysis of 22 studies involving over 2000 children came to this conclusion:

“ Meta-analysis of controlled trials does not support an association between new onset or worsening of tics and psychostimulant use. Clinicians may want to consider rechallenging children who report new onset or worsening of tics with psychostimulant use, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.” (These authors use the term “psychostimulants” to refer to methylphenidate and amphetamine.)

Reference for this study: Cohen SC1, Mulqueen JM2, Ferracioli-Oda E3, Stuckelman ZD2, Coughlin CG2, Leckman JF4, Bloch MH5 (2015). Meta-Analysis: Risk of Tics Associated With Psychostimulant Use in Randomized, Placebo-Controlled Trials. J Am Acad Child Adolesc Psychiatry. 2015 Sep;54(9):728-36. doi: 10.1016/j.jaac.2015.06.011. Epub 2015 Jul 2.

Tourette's disorder is a condition defined by both twitches of the muscles and involuntary vocal sounds. When Tourette's disorder is in its early stages, it very much resembles ADHD. Thus sometimes children are treated with methylphenidate in the early stages of Tourette's disorder, and tics then have their onset later. Probably there have been times when the medication has been blamed for the tics of Tourette's disorder when the tics would have come with or without the medication.

Another complicating factor is that a fairly large number of children go through periods of time when they make twitchy movements of their facial muscles, even without getting medication or having ADHD or having Tourette's disorder. Sometimes people start looking for facial movements because they are informed that these can be a side effect of methylphenidate, when otherwise they wouldn't even think twice about the facial movements that occur.

My overall conclusion is that twitchy movements of the face are very seldom a reason to withhold methylphenidate.

7. Psychosis.

In psychosis, brain function is disrupted enough that one hears or sees things that aren't there, or gets delusional ideas. This is almost never a problem unless the dose of methylphenidate is way too high. Sometimes it's a problem with people who have a disposition to bipolar disorder. There's a possibility that methylphenidate may create bipolar symptoms in people who are so disposed. The side effect of psychosis is one that you should know about, but it is one that is almost never seen when clinicians and patients keep doses in the recommended range.

8. “Zombie-like” appearance.

When children get doses of methylphenidate that are too high, sometimes their facial expressions are bland and unchanging, and they seem much less animated and enthusiastic. I have heard of some people who endured this for a long time; this is a real shame because such symptoms are a clear sign that the dose is too high; this “zombie-like” effect can almost always be eliminated by lowering the dose of medication. This side effect is not a reason not to give medicine. It is a very strong reason to lower the dose if it appears.

9. Causing a manic episode in people disposed to bipolar disorder.

Methylphenidate has actually been recommended as a treatment for depression in people with bipolar disorder. The combination of methylphenidate plus a "mood stabilizer," in one study, resulted in a lower rate of manic episodes, whereas methylphenidate alone resulted in a higher rate. The finding that methylphenidate apparently increases the risk for manic episodes is important, because many people who are bipolar have ADHD symptoms before it is obvious that they are bipolar.

Reference: Viktorin A, Rydén E, Thase ME, Chang Z, Lundholm C, D'Onofrio BM, Almqvist C, Magnusson PK, Lichtenstein P, Larsson H, Landén M. The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder. Am J Psychiatry. 2017 Apr 1;174(4):341-348. doi: 10.1176/appi.ajp.2016.16040467. Epub 2016 Oct 3. Erratum in: Am J Psychiatry. 2016 Nov 1;173(11):1154. PMID: 27690517; PMCID: PMC6641557.

Side effects of the antipsychotic drugs

(Examples: risperidone, quetiapine, aripiprazole, ziprasidone, haloperidol – trade names Risperdal, Seroquel, Abilify, Geodon, Haldol)

1. The possibility of withdrawal psychosis, and the general issue of dependency.

With all drugs that affect the brain, one tends to get effects when the drug is withdrawn that are opposite from the effects the drug had when it was first started. Researchers have looked at the effects of withdrawal of the antipsychotic drugs; these effects include But the most worrisome possibility is that the withdrawal of antipsychotic drugs can worsen or cause psychosis. Psychotic symptoms include hallucinations (seeing or hearing things that aren’t there) or delusions (irrational ideas). A prominent textbook of Pediatric Pharmacology (Martin et al., 2011) lists the following among the effects of “receptor withdrawal/rebound” for the Dopamine D2 receptors that are blocked by the antipsychotic drugs: “psychosis, mania, agitation....” How slowly do you have to withdraw the antipsychotic drugs in order to avoid these effects? The answer is very likely different depending upon how many years one has been on them. How long do these effects last before the neurons can return to the state they were in before the exposure to antipsychotic drugs? Unfortunately, there are not specific answers to these questions.

Reference: Ther Adv Psychopharmacol. 2012 Feb;2(1):13-22. doi: 10.1177/2045125311431105.

Drug-induced supersensitivity psychosis revisited: characteristics of relapse in treatment-compliant patients. Fallon P, Dursun S, Deakin B.

Chouinard G, Samah A, Chouinard V, Peretti C, Kanahara N, Takase M., Iyo M: Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. Psychother Psychosom 2017;86:189–219 DOI: 10.1159/000477313.

2. Tardive dyskinesia

Tardive dyskinesia is an illness whose symptoms are jerky involuntary movements. They particularly often involve the face or the head. They can come often, and can interfere quite a bit with one’s life. These movements are a consequence of the changes in neurons that take place as a result of the antipsychotic drugs’ being given for a long time. They tend to appear when you withdraw the antipsychotic drugs. They tend to go away if you increase the dose of the antipsychotic drugs. But they can appear on a constant dose of antipsychotic drug and gradually get worse.

People divide the antipsychotic drugs into two sets, the first-generation antipsychotics and the second-generation antipsychotics, often called “atypical” antipsychotic drugs. The second generation antipsychotics seem to cause tardive dyskinesia less frequently than the first generation antipsychotics, and indeed this is one of the main reasons why they are chosen. One review (by Carbone et al., below) found that about 25% of people on antipsychotics showed symptoms of tardive dyskinesia, but only about 7% of those who had only taken the second generation drugs had tardive dyskinesia.

Reference: Int J Geriatr Psychiatry. 2015 Dec 17. doi: 10.1002/gps.4399. [Epub ahead of print]

Comparing the risk of tardive dyskinesia in older adults with first-generation and second-generation antipsychotics: a systematic review and meta-analysis. O'Brien A.

Clin Psychopharmacol Neurosci. 2014 Apr;12(1):69-71. doi: 10.9758/cpn.2014.12.1.69. Epub 2014 Apr 24.A case of aripiprazole induced tardive dyskinesia in a neuroleptic-naïve patient with two years of follow up.Goyal R, Devi SH.

Neurol Clin. 2011 Feb; 29(1): 127–viii. doi: 10.1016/j.ncl.2010.10.002 PMCID: PMC3018852

NIHMSID: NIHMS247786 Movement Disorders Induced by Antipsychotic Drugs: Implications of the CATIE Schizophrenia Trial. Stanley N. Caroff, MD, Irene Hurford, MD, Janice Lybrand, MD, and E. Cabrina Campbell, M

Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis. J Clin Psychiatry. 2017 Mar;78(3):e264-e278. doi: 10.4088/JCP.16r10832. PMID: 28146614.

3. Akathisia.

Akathisia means an unpleasant feeling of physical restlessness – the urge to keep moving. Sometimes people with akathisia pace around, or keep changing position while sitting. This goes far beyond the ordinary restlessness that people have when they've been sitting for a long time or feel bored. This symptom can be extremely unpleasant. Sometimes people have increased the dose of antipsychotic drug because they have mistaken akathisia for agitation that is treatable by the antipsychotic drugs. This sometimes makes the akathisia even worse.

This symptom is fairly frequently caused by the antipsychotic drugs. A couple of studies with children and youth have found rates of akathisia in the general vicinity of 10%.

Neurol Clin. 2011 Feb; 29(1): 127–viii. doi: 10.1016/j.ncl.2010.10.002 PMCID: PMC3018852

NIHMSID: NIHMS247786 Movement Disorders Induced by Antipsychotic Drugs: Implications of the CATIE Schizophrenia Trial. Stanley N. Caroff, MD, Irene Hurford, MD, Janice Lybrand, MD, and E. Cabrina Campbell, MD

4. Increased likelihood of diabetes, heart disease, obesity, and other “metabolic” problems.

The second generation antipsychotic drugs tend to cause weight gain, and the appearance of other problems that are associated with weight gain: increased likelihood of diabetes and heart disease. Before those diseases are seen, you may see the effects on blood glucose and the lipids (lipids=fats) in the blood that are signs of early diabetes or that give warnings of atherosclerosis to come later. For this reason, doctors tend to monitor glucose and blood lipids, as well as body weight, when patients are receiving antipsychotic drugs.

Lancet Psychiatry. 2015 Dec;2(12):1092-8. doi: 10.1016/S2215-0366(15)00276-X. Epub 2015 Oct 22.

Effect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study. Foley DL, Mackinnon A, Morgan VA, Watts GF, Castle DJ, Waterreus A, Galletly CA.

5. Effects on the liver

The health of the liver is sometimes checked by measuring the blood levels of enzymes that can be released from liver cells. One of these is called AST (aspartate transaminase) and another is called ALT (alanine transaminase). These enzymes have been abnormally elevated in about one-fifth to about one-half of patients receiving some antipsychotic drugs. The significance of these elevated enzymes is not yet clear.

Drug Metabol Drug Interact. 2014;29(2):123-6. doi: 10.1515/dmdi-2013-0064. Liver enzyme abnormalities during antipsychotic treatment: a case report of risperidone-associated hepatotoxicity.

López-Torres E, Süveges A, Peñas-LLedó EM, Doña A, Dorado P, LLerena A, Berecz R.

6. Dystonias. A dystonia is a side effect that can be scary if one doesn’t realize its cause and realize that it can be treated effectively. In a dystonia, you seem to move into a certain position and only move out of that position by concentrating upon doing so. For example, the tongue sticks out of the mouth and you have to think about it to pull it back in; when you stop thinking about it, the tongue sticks out again. Or the head turns to one side and stays there until you consciously turn it back.

Dystonias are much more frequently seen with the first generation antipsychotics. You can make them go away by giving a drug with anticholinergic effects, such as Benadryl (diphenhydramine).

Neurol Clin. 2011 Feb; 29(1): 127–viii. doi: 10.1016/j.ncl.2010.10.002 PMCID: PMC3018852

NIHMSID: NIHMS247786 Movement Disorders Induced by Antipsychotic Drugs: Implications of the CATIE Schizophrenia Trial. Stanley N. Caroff, MD, Irene Hurford, MD, Janice Lybrand, MD, and E. Cabrina Campbell, MD

7. Parkinsonian symptoms.

The symptoms of Parkinson’s Disease are tremor, rigidity of muscles, unchanging facial expression, and slowed and more difficult movement. The antipsychotic drugs, particularly the first generation ones, can bring on Parkinsonian symptoms. These, like dystonias, are due to the fact that these drugs block the effects of a chemical that sends messages in the brain, called dopamine. These symptoms are reduced by giving a drug that reduces transmission through another chemical called acetylcholine. Drugs like benztropine are sometimes given to counteract the Parkinsonian side effects of the first generation antipsychotics.

Neurol Clin. 2011 Feb; 29(1): 127–viii. doi: 10.1016/j.ncl.2010.10.002 PMCID: PMC3018852

NIHMSID: NIHMS247786 Movement Disorders Induced by Antipsychotic Drugs: Implications of the CATIE Schizophrenia Trial. Stanley N. Caroff, MD, Irene Hurford, MD, Janice Lybrand, MD, and E. Cabrina Campbell, MD

8. The Neuroleptic Malignant Syndrome.

Another name for the antipsychotic drugs is “neuroleptics.” The neuroleptic malignant syndrome is a rare but dangerous side effect of these drugs. People have died from neuroleptic malignant syndrome. It appears to be more dangerous with the first generation antipsychotic drugs than with the second generation drugs. The symptoms are: rigidity of the muscles, fever, fast heart rate, blood pressure that can be too high or too low, and mental changes such as confusion or stupor. To confirm this syndrome, doctors draw blood tests. CPK, an enzyme that comes from muscles and is measured in the blood, is markedly increased in the neuroleptic malignant syndrome. The white blood cell count is also increased. People who develop this syndrome should usually go to an intensive care unit of a hospital, where their temperature and blood pressure can be monitored, and where they may receive medicines that may help this (bromocriptine is one possibility).

Curr Neuropharmacol. 2015;13(3):395-406.Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective.Tse L, Barr AM, Scarapicchia V, Vila-Rodriguez F1.

9. Effects on the hormone prolactin

Both the first and second generation antipsychotics tend to increase the levels of the hormone prolactin. Some are much more active in this side effect than others. Aripiprazole (Abilify) actually has been seen to lower prolactin levels below the baseline levels. Quetiapine is also reputed to be “prolactin -sparing.” Prolactin is meant to stimulate the production of milk in the breasts; elevated prolactin levels from the antipsychotics have been associated with breast enlargement, engorgement, pain, or the production of milk. Elevated prolactin has also been associated with side effects such as loss of periods or lighter or less frequent periods in females, erectile dysfunction in males, and decreased sexual interest. Marked prolactin elevations can lead to a supression of sex hormone production. This in turn can affect the development of sexual organs. The possibility of a delay in sexual maturation in youth has been raised but not proved.

Drugs. 2004;64(20):2291-314. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Haddad PM, Wieck A.

Eur Neuropsychopharmacol. 2008 May;18 Suppl 2:S108-14. doi: 10.1016/j.euroneuro.2008.02.004.

Prolactin awareness: an essential consideration for physical health in schizophrenia.

Montejo AL.

10. Cardiac effects. The antipsychotic drugs have been shown to affect the electrical activity of the heart as measured by the electrocardiogram (EKG), but the frequency with which these drugs cause dangerous effects on the heart such as rhythm disturbances appears to be small. There has not been enough difficulty with cardiac arrhythmias that it is recommended that people routinely get EKG’s before beginning antipsychotic drugs. It is, however recommended that pre-treatment EKG’s be gotten if there is a history of heart illness or symptoms in the person or sudden cardiac death in a first-degree relative.

J Am Acad Child Adolesc Psychiatry. 2015 Jan;54(1):25-36. doi: 10.1016/j.jaac.2014.10.002. Epub 2014 Oct 16. Corrected QT changes during antipsychotic treatment of children and adolescents: a systematic review and meta-analysis of clinical trials. Jensen KG, Juul K, Fink-Jensen A, Correll CU, Pagsberg AK.

11. Hypotension. The antipsychotic drugs can block the alpha-1 adrenergic receptors; their doing this can cause lowered blood pressure or a longer time for the blood pressure to adjust when someone stands up from sitting or lying down. The result can be “postural hypotension” – a feeling of lightheadness or faintness, even actual fainting, when someone stands up after sitting or lying down. The important thing to remember when taking any antipsychotic drug with an alpha-1 blocking effect is that if you feel faint after standing up, quickly lower the head by kneeling down or bending over. This increases the blood pressure in the head and can prevent hurting oneself by fainting.

12. "Neurotoxicity" of first generation antipsychotics.

Several studies have concluded that the "second generation antipsychotics" are better for your brain cells than are the "first generation antipsychotics."

By "first generation" antipsychotics, we mean the ones that have been on the market for 60 years or so: haloperidol, chlorpromazine, fluphenazine, perphenazine, thioridazine and several others. The "second generation" antipsychotics include clozapine, olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, asenapine, and lurazidone, and others; they were approved for use in this country close to the turn of the 21st century. (Each of these has a trade name in addition to the generic names I've given here.)

There have been several studies concluding that the first generation antipsychotics cause a reduction of the gray matter of the brain, and that they do this by several mechanisms that result in the death of neurons. To quote from a review article: "A review of the literature suggests that haloperidol exerts measurable neurotoxic effects at all doses via many molecular mechanisms that lead to neuronal death. A similar effect was observed in 2 other FGAs [first generation antipsychotics]..."

By contrast, the same authors reviewed the second generation antipsychotics and wrote, "A review of the literature suggests that... SGAs exert measurable neuroprotective effects."

The research so far on brain cell death versus protection from cell death points to the conclusion: Don't use the first generation antipsychotics; use the second generation antipsychotics if you need an antipsychotic at all.

Nasrallah HA, Chen AT. Multiple neurotoxic effects of haloperidol resulting in neuronal death. Ann Clin Psychiatry. 2017 Aug;29(3):195-202. PMID: 28738100.

Chen AT, Nasrallah HA. Neuroprotective effects of the second generation antipsychotics. Schizophr Res. 2019 Jun;208:1-7. doi: 10.1016/j.schres.2019.04.009. Epub 2019 Apr 11. PMID: 30982644.

13. Differences exist among the second generation antipsychotics exist with respect to how strong and frequent their side effects are. The point is that choices among these drugs should be made according to which side effects are least worrisome for the given individual.

For example, for risperidone:

weight gain: moderate

effects on blood lipids: low to moderate

diabetes type 2: moderate

prolactin elevation: moderate

effects on QTc interval: low to moderate (this is thought to be a measure of the risk for causing heart rhythm problems)

for aripiprazole:

weight gain: low to moderate

blood lipids (like cholesterol): low

diabetes type 2: low

prolactin elevation: mild reduction

QTc interval on EKG: very low effects

for olanzapine:

weight gain: high

blood lipids: high

diabetes type 2: high

prolactin elevation: low

QTc interval on EKG: low to moderate

for ziprasidone: low for the first 4, but moderate effects on QTc interval

for lurasidone: low for all 5 of these, including reportedly 0 effects on QTc interval