Mechanism of Antipsychotics: We will start with a quick review of some material from my previous video on psychosis. Symptoms of schizophrenia can be broken down into 2 categories, Positive and Negative Symptoms. Positive symptoms include behaviors or sensations that are not normally present. Examples include hallucinations, delusions, catatonia & disorganized speech/behavior. These symptoms are thought to be related to an excess of dopamine. I remember this by remembering that “doPamine has a P in it like Positive”. Negative symptoms are the absence of normal behavior. Examples include a lack of initiative, diminished speech, disheveled appearance & flat affect. These symptoms are thought to be related to an excess of serotonin. As we will see antipsychotics affect dopamine and serotonin to varying levels.
- Mania/Bipolar Disorder
Aypical Antipsychotics [-azine]:
- Haloperidol (Haldol)
- Chlorpromazine (Thorazine)
Atypical Antipsychotics [-apine]:
- Risperidone (Risperdal)
- Ziprasidone (Geodon)
- Aripiprazole (Abilify)
- Quetiapine (Seroquel)
- Olanzapine (Zyprexa)
- Clozapine (Clozaril)
Typical Antipsychotics (AKA 1st Generation or Neuroleptics) primarily block dopamine receptors in a non-specific manor. Therefore, these drugs work best for positive symptoms, and have little effect on negative symptoms. The non-specific mechanism of the drug also means there are lots of side effects. Some of these medications come in a slow release injectable form so they can be used in non-compliant and aggressive patients.
- Neuroleptic Malignant Syndrome (NMS) is a rare but potentially fatal adverse reaction. It involves fever, altered mental status, rigidity and autonomic instability (tachycardia, hypertension, diaphoresis etc.). You may also see elevated myoglobin in blood or urine and elevated Creatine Kinase (CK). Emergently stop the medication, provide supportive care and consider adding Dantrolene (Think DOWN-trolene)
- Extrapyramidal Symptoms (EPS) are due to blockage of Nigrostriatal dopamine. As scary as these may look, they are generally not medical emergencies. In most cases you will continue to use the drug with perhaps a reduction in the dose or the addition of an anticholinergic mediation like Benzatropine or Diphenhydramine. Tardive Dyskinesia is the exception and requires cessation of the medication as it can be permanent. Usually you would switch a patient with TD to a 2nd gen antipsychotic.
- Akathisia = sensation of restlessness
- Acute Dystonia (involuntary continuous muscle contractions often of the neck)
- Oculogyris Crisis = eyes get locked looking upward and they have to lean over to see
- Dyskinesia (AKA Pseudoparkinsonism) presents like Parkinson’s Disease with symptoms like pill rolling tremor, cogwheel rigidity & bradykinesia (or slow movement)
- Tardive Dyskinesia (TD) = uncontrollable facial tics, grimacing & tongue movements
- Hyperprolactinemia (due to Blockage of Tuberoinfundibular dopamine) → galactorrhea, gynecomastia, decreased libido and menstrual irregularities.
- Anticholinergic effects of sedation, orthostatic hypotension, dry mouth, constipation etc.
- QT Interval Prolongation
Atypical Antipsychotics (AKA 2nd Generation Antipsychotics) block dopamine and serotonin receptors meaning they treat positive and negative symptoms. They also may have improved specificity which limits side effects when compared to typical antipsychotics. They are largely used as first line medications instead of the 1st generation antipsychotics.
You can still get all of the same side effects as you do with the typical antipsychtoics, but at least in theory they should be much less common. In particular Risperidone has a side effect profile closer to the typical antipsychotics as it has EPS and hyperprolactinemia more commonly than the other 2nd gens. Clozapine and Quetiapine are the least like the typicals as they essentially never have EPS or high prolactin. So if you are using a typical antipsychotic and have to switch meds based on the side effects, Quetiapine is probably your best option. Like some of the 1st Gens, most of the 2nd Gen Antipsychotics also commonly have sedation as a side effect. QT prolongation is another side effect seen in both classes. It is especially common in Ziprasidone.
Another important side effect for Atypicals is Metabolic Syndrome (diabetes, weight gain, hyperlipidemia etc.). So patients on atypical antipsychotics should have their weight, blood pressure, blood glucose and lipids monitored regularly. Olanzapine & clozapine are the worst for causing metabolic syndrome so they should be avoided in patients who have diabetes or obesity. Ziprasadone and Aripiprazole cause metabolic syndrome less than the other 2nd gens.
Clozapine is the “prototype” for the atypical antipsychotics as it was the first one developed and has higher efficacy. However, it isn’t used nearly as much as the others because it causes agranulocytosis and seizures. This drug is usually reserved as a last resort if the other options don’t work. Patients on Clozapine needs to have a CBC very frequently to monitor for agranulocytosis. If a low WBC count is found the medication needs to be discontinued to prevent life threatening infections.
Mood Stabilizers are a group of medications that help to steady and/or prevent intense mood swings. These medications are used primarily for Bipolar Disorder and Schizoaffective Disorder. As we have already discussed many antipsychotic medications can have a mood stabilizing effect. They are a first line treatment for mania when there are psychotic features and/or you need a fast onset of action. However, when we use the term Mood Stabilizer we are generally talking about Lithium and anticonvulsants rather than antipsychotics. Mood Stabilizers require gradual titration and take about 1 week to kick in so they are not as useful in the acute setting. However, for long term treatment they are often the treatment of choice for Bipolar Disease. A combination of an antipsychotic and a mood stabilizer is often used for Bipolar Disorder as it usually works better than monotherapy for acute management and relapse prevention.
Lithium is the first line mood stabilizer according to most guidelines and textbooks, but in practice many psychiatrists use other medications first due to better side effect profiles and other considerations that make it easier to prescribe. Lithium has a narrow therapeutic window which means dosing can be difficult and requires close monitoring with Lithium Blood Levels (which correlate with efficacy). The mechanism of Lithium is not very well understood.
- Lithium Toxicity (AKA Lithium Overdose) may occur acutely from intentional or unintentional large doses of lithium or chronically from a prescribed lithium dose that was not properly titrated. It can present with nausea/vomiting, diarrhea, tremors, altered mental status, incoordination, and seizures. If these symptoms arise the Lithium treatment should be discontinued immediately to prevent fatal consequences.
- Lithium is a teratogen that causes cardiac deformation in the fetus so it should not be used in anyone who is or may become pregnant.
- Lithium commonly causes Hypothyroidism
- Lithium is nephrotoxic and can cause Nephrogenic Diabetes Insipidus (thirst, polyuria etc.).
- Before you start the medication and regularly after initiation you should get a pregnancy test, thyroid level and creatinine test to monitor for the onset of side effects.
Anticonvulsants: Some, but not all, epilepsy drugs can be used as mood stabilizers. These drugs are known to be hepatotoxic so regular liver function tests (LFTs) should be performed. A CBC should also be checked as these drugs can have hematologic effects such as Thrombocytopenia.
- Valproate or Valproic Acid (Depakote) is the most commonly used anticonvulsant for Bipolar Disorder. It is associated with spina bifida, so you have to give folate to patients if they are trying to get pregnant. It is also associated with pancreatitis.
- Carbamazepine (Tegretol) & Lamotrigine (Lamictal) are alternatives. They are associated with rashes and severe hypersensitivity reactions like Stevens Johnson Syndrome. They can also lead to an increased metabolism of the hormones is oral contraceptives. This is obviously a bad thing considering the drug is also a teratogen.
Anxiolytics & Benzodiazepines (Benzos)
Anxiolytics are a group of medications that relieve or abort anxiety. SSRIs/SNRIs are considered first line pharmacologic treatment for Generalized Anxiety and Panic Disorder. We discussed these types of medication in depth in our previous video on antidepressants, and most of them do have anxiolytic properties. The only real difference is that higher doses are usually needed to treat anxiety than depression. Cognitive Behavioral Therapy has similar efficacy to SSRIs/SNRIs and is also considered a first line treatment. The best treatment option may be a combination of an antidepressant with CBT. The downside to both of these 1st line options is that they take about a month to start working. Benzos and TCAs are considered second line medications. Beta Blockers like propranolol are not true anxiolytics, but they can help mask some of the symptoms of anxiety such as palpitations.
Buspirone (or Buspar) is another treatment option to consider for GAD, but it does not work for Panic Disorder. It is a non-benzo anxiolytic that functions by acting as a partial serotonin agonist. It does not have the risk of dependence, abuse, or withdrawal like Benzos and does not have nearly as much sedation. However, Buspirone does take a couple weeks to kick in.
Benzodiazepines increase the effects of Gamma-Aminobutyric Acid (an inhibitory neurotransmitter) by increasing GABAs affinity for the receptor and increasing the frequency of the Cl channel opening. Benzodiazepines are great at aborting acute anxiety and panic attacks quickly. They have a much faster onset of action than other anxiolytics. However, Benzos don’t work very well to prevent anxiety and panic attack prophylactically. Perhaps the best use for Benzos is in addition to an SSRI/SNRI. You can start both together and then after about a month when the SSRI has started working you can taper off the Benzo.
Benzos are largely considered safe for short term use, but long term use is very controversial due to the risk of abuse, dependence, sedation and withdrawal. These medications are generally contraindicated in those with a history of substance abuse, and use in elderly populations should be limited due to the increased level of risk of adverse events. Scheduled long acting doses are preferred, because as needed use of short acting benzos has a higher risk for psychologic dependence.
Benzos usually end in “Zepam” or “Azolam.” They are broken down into short acting, intermediate acting and long acting groups. However, short acting Benzos aren’t used as much and are lower yield for the exam so I haven’t listed them.
- Lorazepam (Ativan)
- Alprazolam (Xanax)
- Temazepam (Restoril)
- Clonazepam (Clonipin)
- Diazepam (Valium)
My last video in the Psych section was on substance abuse and discussed things like Benzo overdose and withdrawal, so go watch that one if you haven’t already. I have also already covered the use of benzo for alcohol withdrawal so I won’t cover that here. Later when I make the neuro videos I will cover things like the use of Benzos for seizures or status epilepticus.
Benzos also have action as Hypnotic medications and can be used for the short-term treatment of insomnia. However, their use should be limited to a few weeks duration due to the risk of dependence. It is preferred that Benzos be used intermittently and at the lowest effective dose. Higher doses of Benzos are needed for a Hypnotic effect when compared to anxiolytic action. There are also non-benzo hypnotics that are at least in theory safer options for long term use. This would include drugs like Lunesta and Ambien, but this topic is very low yield for the Step 1 exam so I will skip it.