- Hydroxyzine is a medication I’m very familiar with, it’s used as an as needed medication for anxiety and insomnia on my inpatient unit.
- Hydroxyzine is a histamine receptor antagonist or antihistamine with anticholinergic properties like diphenhydramine.
- It’s FDA approved for several things, but my favorite is anxiety and tension associated with psychoneurosis. Several other indications include anxiety associated with organic disease states, premedication sedation, and anxiety withdrawal symptoms in alcohol use disorder.
- The mechanism is very simple it blocks histamine H1 receptors, not much else to say about it.
- The usual dosing for anxiety is 50-100 mg 4 times per day according to the FDA, but I would use caution with the dosing because in 2015 the European Medicines Agency announced a small but definite risk for QT interval prolongation and torsade de pointes in persons using hydroxyzine. It’s best to keep adult doses at 100 mg/day or less and 2 mg/kg/day in children weighing up to 40 kg.
- If possible, avoid hydroxyzine in the elderly or limit the dose to 50 mg/day
- For dosing be sure to use hydroxyzine in the lowest effective dose, avoid it in patients with known risk factors for cardiac arrhythmias or on medications that can increase the risk of QT prolongation.
- The anticholinergic activity of hydroxyzine is much lower than that of diphenhydramine, it’s more selective for the histamine receptors. There can still be some risk of cognitive impairment due to anticholinergic activity.
- Hydroxyzine is highly lipophilic and easily crosses the blood-brain-barrier.
- The half-life is around 24 hours
- Other common side effects include sedation, dry mouth, and tremor
- Hydroxyzine is contraindicated in early pregnancy and not recommended for breast feeding mothers.
- To sum things up, this medication offers an option for the short-term treatment of anxiety that is not addictive. It still has some risks and like most medications that target anxiety is not meant for long term management.
-This is one of the only disorders where medication is the first line treatment in children and adolescents.
-There is a 70%-80% response rate to psychostimulants, and medication consistently outperforms behavioral interventions in RCTs.
-For preschool age children, behavioral interventions are first line and medications are considered if there is a poor response to behavioral intervention and functional impairment.
–Methylphenidate (MPH or Ritalin) should be started at 2.5 to 5 mg twice daily (before breakfast and lunch). It can be increased by 2.5 to 5 mg/day reaching an optimal dose of 1 mg/kg/day and a maximum dose of 2 mg/kg/day.
–Side effects include insomnia, decreased appetite, mood disturbance, tics, headaches, GI distress, and rarely psychosis.
-There are several long-acting preparations including Ritalin XR, Ritalin LA, metadate, Concerta, Daytrana, Focalin XR and several others. The important point about long-acting preparation is they provide a sustained second release with resulting plasma levels lasting 4-12 hours depending on the preparation.
–Amphetamine sulfate (Adderall): should be started at 2.5-5 mg once or twice per day. It can be increased by 5 mg per week with an optimal dose of 0.5-1 mg/kg/day. Dextroamphetamine is twice as potent as amphetamine. The side effect profile is similar to MPH.
Longer-acting amphetamine preparations include Adderall XR, Dexedrine, Dyanavel XR, and Vyvanse (formulated as a prodrug to reduce the risk of abuse). These will provide coverage for about 12 hours.
-There is a black box warning for the risk of abuse and dependence. In addition, there is a cardiovascular safety warning regarding the risk of sudden cardiac death in children and adolescents with structural heart defects or other severe cardiac conditions. Patients should be screened for any cardiovascular disorders, family history of sudden cardiac death, and an EKG should be performed.
-ADHD is the most common physiocratic disorder in children.
-Its prevalence is 5-11% in school-aged children
-It often presents with a classic triad of inattention, hyperactivity, and impulsivity
– However, it can present as mixed, or primarily inattentive or hyperactive
-Symptoms must include at least 6 signs of inattention and/or six signs of hyperactivity/impulsivity for 6 months.
-For patients 17 years and older on 5 symptoms are required
Symptoms of inattention include:
-failure to pay close attention
-difficulty sustaining attention on tasks or activities
-failure to listen when spoken to
-difficulty organizing tasks
-avoidance of activities that require mental effort
-losing things necessary for tasks or activities
-distractibility and forgetfulness in daily activities
Symptoms of hyperactivity:
-fidgeting with hands or feet
-inability to sit still
-running around when not appropriate
-difficulty engaging quietly in activities
-feeling on the go or driven by a motor
Symptoms of Impulsivity:
-answering questions before they are completely asked
-having trouble waiting ones turn
The pattern of behavior must be more severe and occur more often than in other children of the same age. The symptoms of the disorder must be present before the age of 12 years. The diagnosis can be made after 12 years of age but there must be evidence of symptoms before the age of 12. The last important point is the symptoms must occur in two different settings (e.g., home and school).
Many patients may be familiar with screening scales like the Vanderbilt or Conners which can be used to help confirm the diagnosis usually one is completed by the parent the other by a teacher.
Mirtazapine is considered a noradrenergic and specific serotonergic antidepressant. It’s one of a newer generation of medications used to treat major depression.
The mechanism is unique, and the noradrenergic effects are mediated by blockade of alpha-2 presynaptic receptors which results in an increase in norepinephrine. This is a negative feedback loop, which means norepinephrine in the synaptic cleft will bind to presynaptic alpha-2 receptors resulting in decreased norepinephrine release (hence the negative feedback). If we block the alpha-2 receptors preventing norepinephrine from binding it will allow more norepinephrine to be released. Essentially, we are taking the break off.
Mirtazapine is also a histamine H1 receptor blocker which is the reason for many of the side effects including sleepiness and weight gain.
The dose is usually 15 mg at bedtime and can be increased every 1-2 weeks to a maximum dose of 45 mg at bedtime. In some cases, doses of up to 90 mg at bedtime have been used.
If the goal is sedation and help with sleep a 15 mg tab can be broken in half to 7.5 mg which is more sedating than 15 mg. Sedation associated with the affinity for H1 receptors and typically experienced at dosages of 15 mg/day may be counteracted by an increasing noradrenergic neurotransmission at dosages of 30 mg/day. The main point is higher doses result in less sedation because of increased noradrenergic effects.
Be mindful of the propensity for weight gain with this medication. BMI and waits circumference should be monitored.
The most common side effect of mirtazapine is sleepiness (54%), dry mouth (25%), increased appetite (17%), constipation (13%), weight gain (12%), weakness, dizziness, and flu like syndrome.
This is a good choice for a depressed patient with difficulty sleeping, and poor appetite. It’s also a good choice for a patient who is concerned about sexual side effects. If a patient is concerned about weight gain and sleepiness this may not be the best medication for that person. It works well in combination with venlafaxine of desvenlafaxine. There is some evidence to support the use of mirtazapine in combination with haloperidol to treat the negative symptoms of schizophrenia.
Desvenlafaxine is the active metabolite O-desmethylvenlafaxine (ODV) of venlafaxine and is formed as a result of CYP450 2D6. It shares many of the same properties as venlafaxine.
- It’s FDA approved for Major depressive disorder
- Mechanism of action: This medication will boost the neurotransmitters serotonin, norepinephrine, and dopamine. It does so by blocking the serotonin reuptake pump, the norepinephrine reuptake pump, and increases dopamine in the frontal cortex because dopamine is largely inactivated by the norepinephrine reuptake pump in the frontal cortex.
- The dosing is a little easier than venlafaxine. You can start with 50 mg/day with a maximum dose of 100 mg/day. In some cases, doses of 400 mg/day have been shown to be effective but there is increased risk for side effects at higher doses.
- Desvenlafaxine is more potent at the serotonin transporter but has greater norepinephrine transporter inhibition relative to venlafaxine. This is one advantage along with lower does required to achieve that inhibition.
- These tablets should not be broken, crushed, or chewed, it will alter the controlled release.
- It has some of the same issues as venlafaxine when it comes to withdrawal or discontinuation. It can be difficult to taper off and may require starting fluoxetine prior to tapering.
- Blood pressure must be monitored regularly during treatment.
- Most common side effects include: nausea (most common 12%), dizziness (8%), increased sweating (6%), constipation (5%).
- Other side effects: decreased appetite, decreased libido, erectile dysfunction, abnormal dreams, tinnitus, vertigo
- I’ve had many questions about combining this with mirtazapine. It can be combined with mirtazapine. Trazodone and bupropion are other popular medications to combine with desvenlafaxine if monotherapy does not result in remission.
- Desvenlafaxine offers some benefits over venlafaxine including more consistent plasma levels due to lack of metabolism by CYP 2D6, it has more potent action at the norepinephrine transporter than venlafaxine. It may be a better option if you are targeting the norepinephrine system.
- The only FDA approved use of trazodone is for depression. However, this medication is rarely prescribed for this purpose. The higher dose requirements and lower affinity for the serotonin transporter allows the side effect profile to make the medication intolerable for most patients.
- The most common way it’s used is as an adjunctive therapy for sleep disturbances secondary to depression.
- The mechanism of action is blockade of serotonin 2A receptors and blockade of the serotonin reuptake pump.
- Dosing: To take advantage of the sedating properties you want to use a lower dose. A dose of 25-150 mg/night is appropriate. For depression the dose must be much higher anywhere from 150-600 mg/day
- For depression start with 150 mg/day in divided doses (short half-life) and increase every 3-4 days by 50 mg/day as needed to a target dose of 400 mg/day. For insomnia start with 25-50 mg/night and increase as tolerated to a target dose of 50-150 mg/night. That same target range of 50-150 mg/day can be used if trazodone is being added as an adjunct therapy for depression.
- It’s very important to start low and go slow when increasing the dose. Patients can have carryover sedation, ataxia, and intoxicated like feeling if titrated too rapidly.
- Do not stop the medication prematurely. In difficult to treat patients’ higher doses may be required 150-300 mg or up to 600 mg in some cases.
- It’s ideal to try and limit dosing to once nightly at bedtime to avoid daytime sedation
- Notable Side effects: Nausea, vomiting, constipation, dry mouth, dizziness, sedation, fatigue, headaches, life threatening side effects include priapism (1 in 8,000 men), seizures, activation of suicidal ideation in patients under 24 years of age.
- The onset of therapeutic actions for insomnia should be immediate once an adequate dose is reached. There is no evidence of tolerance, abuse potential, or withdrawal.
- Therapeutic action for depression is delayed by 2-4 weeks if it’s not working by 6-8 weeks consider a dosage increase or switch depending on dosage reached
- Trazodone offers a nonaddictive option for insomnia treatment and can be used as an adjunct for depression treatment. It’s less likely than other antidepressants to cause sexual dysfunction. It may be less likely to precipitate hypomania or mania and may have some benefit for treating agitation and aggression associated with dementia.
I will talk about sedative and hypnotic medications in future videos, but I want to start a discussion on sleep with sleep hygiene. I recommend all my patients start here and follow this process at least 90% of the time prior to talking about medication. I find most patients are not doing these things and if they are it’s not consistent enough to see a noticeable improvement.
- Stick to a routine by waking up at approximately the same time each day. Do this for seven days, and do not alter the time on weekends. This will help you gradually set your internal clock. You have more control over your wake times than your sleep time as you may not feel tired. Try to avoid taking a nap during the day even on nights where you do not get much sleep.
- Avoid all caffeine after 12 PM, the effects of caffeine are long lasting and can interrupt sleep. If you can completely stop caffeine that would be best, but at the very least minimize consumption before 12 PM.
- Try to exercise daily (seven days per week), preferably early in the day and not too close to bedtime. Start with 15 minutes per day and gradually work your way up. A combination of resistance training and cardiovascular training is best.
- Stop doing active mental work at least one hour before bed.
- Avoid watching TV, using a phone, laptop, or tablet before bed. The blue light from screens has been shown to worsen sleep. The bed should be used for sleep and sex only.
- Create a bedtime ritual to follow every night before bed, warm bath, mindfulness exercise, gratitude journal, reading, or listening to music.
- Do not use alcohol as a way to promote sleep. Alcohol negatively impacts sleep architecture and the sleep you do get will be unsatisfying.
- The bedroom should be dark, quiet, and the temperature should be cool but not cold around 65 degrees is ideal. Consider blackout curtains, a fan to cool the room, and ear plugs to facilitate these conditions.
- Restrict Food and drink 2-3 hours prior to bedtime. This will reduce the chances of sleep being interrupted to use the bathroom.
- If you have any pain, take appropriate pain medications prior to bed.
- Quetiapine offers some benefits over other dopamine blocking medications. It has a much lower risk for EPS and a broad spectrum of effects. The main limitations are weight gain, sedation, and orthostasis. The extended-release formulation offers a once nightly dosing that can reduce daytime sedation.
- It has a number of FDA approved indications including use in schizophrenia, bipolar disorder, bipolar depression, and major depression as an adjunct
- It’s mechanism of action is blocking dopamine D2 receptors which targets positive symptoms of psychosis and serotonin 2A receptors which enhance dopamine release in certain regions of the brain reducing motor side effects and possibly improving cognitive side effects. It’s effects on depression and bipolar depression may be related to 5HT1A partial agonist activity, norepinephrine reuptake blockade, and 5HT2C and 5HT7 antagonist properties.
- Clinically quetiapine is often underdosed and stopped or switched before an adequate trial is completed. Higher doses generally achieve greater response for manic or psychotic symptoms.
- For schizophrenia start with 25 mg BID or 300 mg XR QHS. Target doses 400-800 mg/day
- For bipolar start with 50 mg BID or 300 XR QHS. With a target dose of 400-800 mg daily for mania and 300 mg/day for depression (studies indicate that 600 mg was not better for depression than 300 mg)
- For depression start at 50-100 mg/day in divided doses with a target of 150-300 mg/day (data indicates that 150 mg and 300 mg do equally well so either dose is appropriate depending on patient response)
- You can increase the dose 50-100 mg/day every 1-4 days to a target dose
- The max daily dose in adults is 800 mg/day, occasionally patients may require 800-1,200 mg/day for psychosis or mania
- Monitoring is similar to other dopamine blocking medications, specifically fasting blood glucose and lipid profile, BMI, blood pressure
- Side effects include sedation, hypotension, dry mouth, dizziness, constipation, weight gain and fatigue. Watch for orthostatic hypotension at high doses or with rapid titration. There is essentially no motor side effects or prolactin elevation.
- For XR formulations do not crush or chew them, if a patient has been off the medication for more than 1 week you want to restart as if initial therapy. Quetiapine has some abuse potential reported in the literature particularly in incarcerated populations
- In the initial studies with beagle dogs cataracts developed but human studies have not shown this association
- The gut microbiome consists mostly of bacteria and that is largely the portion of the microbiome we are focusing on (fungi and viruses exist but their function is largely unknown)
- Communication pathways exist between the microbiota-gut-and brain.
- Multiple mechanisms exist that allow gut microbiota to signal to the brain and control physiological processes.
- These include release of gut peptides from enteroendocrine cells which activate receptors of the immune system and vagus terminals in the gut.
- Studies indicate that these bacteria can manufacture and secrete essential neurochemicals including serotonin, dopamine, NE, GABA, and acetylcholine
- Depression and anxiety have been linked to a less well diversified gut microbiome.
- What can help diversify the gut microbiome? Diet, processed food, sugar, saturated fats, and red meat. Medication can also alter the gut microbiome, a good example is oral antibiotics used to treat an acute infection, sleep, exercise. Sounds a lot like a healthy lifestyle will get you the microbiome you need for optimal mental health.
- However, if you want a treatment there have been several studies that looked at fecal transplant to treat psychiatric disorders. Fecal transplants are much easier these days and now there is a capsule version that you take orally. There is not enough data to recommend this as a practical treatment and if the patient goes back to eating a poor diet, sleeping poorly, not exercising then the gut microbiome will revert after the transplant.
- What are the practical things you can do? Stop eating processed food, sugar, and red meat. Increase your fiber intake and select a diet like the Mediterranean diet or a plant based whole food diet that will provide those prebiotics. You could supplement with a probiotic but most of what you need can be had from a good diet alone and I think it’s far better to change the diet then to try using supplements to treat a poor diet. Fermented products like kimchi, kombucha and sauerkraut are good sources of live bacteria.
- If you choose to take a probiotic make sure it’s a quality, 3rd party tested product.
- Increase aerobic activity, I think if you goal is overall general health and you have limitted time, I think aerobic activity is a better bang for your buck.
- The way I believe you get and keep a healthy gut microbiome is through lifestyle modification. Improving your diet, exercise, and sleep is a good place to start. If you want to supplement with food products like kimchi or kombucha, go for it. I do not believe there is enough evidence to support a probiotic supplement for psychiatric disorders at this point, but if you want to spend $30 or more per month on a product if it’s a quality one that’s fine. Remember you cannot supplement away a bad diet.
Aripiprazole is a dopamine serotonin receptor partial agonist. Influencers like Joe Rogan have commented on this medication in past shows and there seems to be a lot of controversy surrounding its use in depression specifically.
- It’s approved for schizophrenia, acute mania/mixed mania, bipolar maintenance, depression (adjunct), autism related irritability, Tourette’s disorder, and acute agitation in schizophrenia or bipolar disorder in the IM form.
- This is a unique medication among dopamine blocking drugs, it acts as a partial agonist at dopamine D2 receptors.
- What does this mean? Theoretically it reduces dopamine output in states of excessive dopamine production such as schizophrenia mediating the positive symptoms (e.g. hallucinations) of the disorder.
- Now how does it work to improve mood? Here it’s a similar concept, if dopamine levels are low, the partial agonism will increase dopamine output resulting in improved cognitive, negative, and mood symptoms
- There are several other receptor interactions associated with aripiprazole including D3 receptor activity, partial agonism at 5-HT1A receptors, blocks 5HT2A receptors which increases dopamine in some areas of the brain, blockade of 5HT2C and 5HT7 receptors which may contribute to the antidepressant effects.
- With Aripiprazole what you see is about a 60% dopamine blockade because of this partial agonist mechanism. Brexpiprazole (rexulti) has even less dopamine blockade about 20% overall do. This would theoretically worsen psychosis but would possibly help with depression.