All medications have side effects. In fact, medication side effects can be used to a clinician’s advantage when making a decision on what medication to initiate. When clinicians are being trained, they are often taught medications by class. This makes for an easy way to remember what class is used for what purpose and in general, what to expect from that medication. In psychiatry, antipsychotic medications are a mainstay of treatment. Whether you are learning of these medications for the first time or are trying to study for a board exam, it is important to be able to recognize key differences among antipsychotic medications. In this post, I will review key side effects of antipsychotics and how certain medications are more likely to produce specific side effects.
First and second generation antipsychotic medications are dopamine blockers. These medications are first-line when treating psychotic symptoms such as hallucinations, delusions, and bizarre or disorganized behavior. These symptoms are known as the positive symptoms of schizophrenia or are the symptoms that are “added to” a person. However, schizophrenia is not the only condition where symptoms such as hallucinations can be seen. They can be present in acute mania, depression with psychotic features, substance use disorders, among other conditions. Often times, these symptoms are frightening to the patient, their friends, and family.
The aforementioned symptoms are caused by excessive dopamine production and activity in the mesocortical and mesolimbic tracts. Prior to 1990, clinicians would treat these conditions with typical or first-generation antipsychotics (FGAs). These medications include drugs such as chlorpromazine or haloperidol and are strong antagonists of dopamine receptor D2. While numerous studies have proven their effectiveness at treating psychotic features, they have a higher rate of extrapyramidal symptoms (EPS). EPS are one of the main reasons patients stop taking the medication as these symptoms can cause significant distress. Another problem with FGAs is they do little to nothing to address negative symptoms such as avolition or thought blocking.
Second-generation antipsychotics (SGAs) were first introduced in 1990 with the development of a medication called clozapine. SGAs include dopamine antagonism, making them effective at treating positive symptoms, but also include mixed antagonism and agonism at 5HT, making them more effective at treating negative symptoms. In general, SGAs have a lower affinity for the D2 receptor, causing less EPS, and improving patient adherence. However, these medications come with their own side effects that can cause problems for the patient.
Below is a list of side effects, a brief overview of why they happen, and how they are treated:
EPS adverse effects such as bradykinesia (slowing of movements), akathisia (motor restlessness), dystonia (muscle spasms contractions such as torticollis), Parkinsonian syndrome (rigid muscles): Problems such as bradykinesia or Parkinsonian emanate from D2 blockade in the nigrostriatal tract, resulting in less dopamine but more acetylcholine. To reduce the excess acetylcholine, an anticholinergic drug such as benztropine is prescribed, which will block the action of acetylcholine. Patients who are on FGAs are typically prescribed benztropine prophylactically to prevent EPS. Some SGAs, such as quetiapine, have anticholinergic properties, which provide D2 blockade but also protect against these effects.
Acute dystonia can happen hours to days after starting an antipsychotic medication. These are disturbing muscle spasms or contractions and are particularly uncomfortable for patients. Acute dystonia is a medical emergency and requires immediate intervention. Dystonia is treated with anticholinergic drugs such as benztropine or diphenhydramine.
Akathisia or motor restlessness can be observed by the clinician or can be a subjective complaint of the patient. This is a side effect patients really notice and one that can have severe consequences. Think of akathisia as “ants in your pants.” This can be so intense it can actually lead to an increased risk of self-harm. Akathisia can be treated with a benzodiazepine or a beta-blocker such as propranolol. Often, the best treatment is to stop the offending agent to a different medication with less risk.
Tardive dyskinesia (TD): By definition, this is something patients experience after they have been on an antipsychotic medication for an extended period of time and is another big reason why FGAs have fallen out of favor to SGAs. When a patient has tardive dyskinesia, they will experience involuntary repetitive muscle movements, most commonly in the face or trunk. Observable effects include grimacing, tongue movement, lip smacking, eyebrow movements, and eye blinking. TD is caused by an increase in dopamine receptors due to constant dopamine blockade. These receptors are overly sensitive or upregulated. Treatment for TD is complicated and the best course of action is usually to switch from a FGA to a SGA. Pharmacological treatment options are geared toward the specific impairment and can be treated by benzodiazepines or tetrabenazine. Benztropine, a treatment for EPS, can actually make TD worse as you are turning off the parasympathetic nervous system (rest and digest) with an anticholinergic agent.
Weight gain: As stated, SGAs have replaced FGAs in most cases as first-line agents due to their lower risk of causing EPS and TD. However, they are not without their own problems. Many SGAs cause increased weight gain, leading to metabolic syndrome. Patients started on SGAs require close monitoring of their lipid panels, waist circumference, blood pressure, and blood glucose. Patients should be educated about the need for good dietary practices and the need for routine exercise. Some patients on SGAs may end up needing treatment with metformin, cases when many psychiatric clinicians will refer back to a patient’s primary care provider or endocrinologist.
Hyperprolactinemia: When dopamine is blocked in the tuberoinfundibular pathway, prolactin increases. This can cause gynecomastia and amenorrhea. Like EPS and TD, this was more common in FGAs. In fact, clinicians used to check a patient’s prolactin level to determine whether or not they were taking their antipsychotic medication. Not all SGAs are immune from the risk of hyperprolactinemia, as risperidone, which is the SGA with the highest affinity for D2, and paliperidone can cause this. If using one of these drugs, baseline prolactin levels can be drawn.
Agranulocytosis: This occurs when a patient’s absolute neutrophil count (ANC) is less than 100 neutrophils per microliter of the blood and is exclusive to clozapine. Because this is a condition that can be life-threatening, clozapine, despite being the first SGA, is not for first-line use. Patients can only be prescribed clozapine after they have failed two other antipsychotic medications, one of which should be a non-clozapine SGA. Clozapine is a medication where a risk evaluation and mitigation strategy is deployed.
Neuroleptic Malignant Syndrome (NMS): This is the most severe potential adverse effect of antipsychotics and is a medical emergency. A good way to remember NMS is, “hot, stiff, and out-of-it.” NMS is characterized by muscular rigidity, hyperthermia, altered consciousness, and autonomic dysfunction. It is treated by discontinuing the offending agent, supportive care, and a muscle relaxer called dantrolene.
All medications have side effects, and clinicians should always take the time to educate patients on the risks before starting a medication. It is imperative when learning these medications that you familiarize yourself with the most common side effects of the agent. This is by no means meant to be a comprehensive list but is hopefully helpful in differentiating certain key points.
This post was written by Richard Gray, MSN, APRN, PMHNP-BC. The above information is for educational/entertainment purposes and is not intended to be treated as medical advice. If you have questions about a medication you are taking, discuss these questions with your medical provider.