›

Antipsychotics & Lithium

Notes

Antipsychotics & Lithium

Sections






  • Here we'll learn about the psychopharmacology of antipsychotic agents and lithium.

Clinical Use

  • To begin, start a table.
  • Let's address where we use antipsychotics and lithium in clinical practice.

Antipsychotics

Primary Use

Schizophrenia

  • Both in acute psychosis and as chronic maintenance therapy.
    • See the following tutorial for details regarding schizophrenia.
    • For reference, catatonia is generally managed via intravenous benzodiazepines (rather than antipsychotic agents).

Bipolar disorder

  • Specifically the mania but also as maintenance therapy.

Schizoaffective disorder

  • Schizoaffective disorder is similar to schizophrenia but has more prominent mood symptoms and less overall decline in functioning.

Additional Uses

Tourette syndrome

  • Tourette syndrome is an involuntary movement disorder, and, as we'll see, these drugs have the ability to suppress movement.

Nausea

  • Nausea, research on an anti-emetic phenothiazine called chlorpromazine helped in the discovery that anti-dopaminergic properties could be beneficial in psychosis (prochlorperazine is preferred, now, instead for nausea, because it has fewer extrapyramidal side effects).

Delirium

  • Short or longer term management of delirium and hallucinations.

Miscellaneous

  • There are various other instances where antipsychotics are used.

Lithium

Bipolar disorder

  • Lithium is primarily used in the treatment of bipolar disorder.

Antipsychotic Mechanisms of Action

Antipsychotic Classes

We generally divide antipsychotic agents into: 1st generation (aka typical) and 2nd generation (aka atypical) agents.

1st Generation (aka Typical) Antipsychotics: D2

  • In brief, indicate that 1st generation agent antipsychotic effects are primarily from D2 (dopaminergic) receptor inhibition.
    • Note that we subdivide the 1st generation antipsychotics into high-potency (strong D2 inhibition) and low-potency (less D2 inhibition) agents.
    • Low-potency agents have greater anti-histamingeric and anti-cholinergic effects at their effective doses but lower potential for extrapyramidal side effects.
    • Review the list of antipsychotics at the end of this tutorial for details about their potencies.

2nd Generation (aka Atypical) Antipsychotics: D2, 5HT2A, Alpha-adrenergic

  • 2nd generation agent effects are primarily from D2 (dopaminergic) receptor inhibition; 5HT2A (serotoninergic) receptor inhibition, and alpha (adrenergic) receptor inhibition (both alpha 1 and alpha 2 receptors have been implicated).

Additional Receptors: D4, mAChR, H1

  • Antipsychotics also widely inhibit D4 (dopaminergic) receptors (with little or no apparent therapeutic benefit), M (muscarinic) acetylcholine (ACh) receptors (mAChR), and H1 (histaminergic) receptors, as we'll see this inhibition has significant side effects.

Let's take this opportunity to review a simplistic approach to key central nervous system dopaminergic pathways, which can help us infer the effects of these drugs.

Ventral tegmental area (VTA): Dopamine

Mesocortical Pathway

  • Ventral tegmental area projects to the prefrontal cortex.
  • This pathway is involved in behavior/executive function.
  • Dopamine hypothesis of Schizophrenia:
    • Hypodopaminergic activity in D1 receptors in this pathway produces negative symptoms in schizophrenia (eg, apathy).

Mesolimbic Pathway

  • Ventral tegmental area projects to the limbic area, especially the nucleus accumbens in the forebrain.
  • This pathway is involved in emotion.
  • Dopamine hypothesis of Schizophrenia:
    • Hyperdopaminergic activity in D2 receptors in this pathway produces positive symptoms in schizophrenia (eg, hallucinations).

Dopamine Hypothesis

  • Hypoactivity in the dorsolateral, prefrontal cortex (mesocortical pathway) produces NEGATIVE symptoms of schizophrenia (eg, apathy).
  • Hyperactivity in the ventromedial, limbic area (mesolimbic pathway) produces POSITIVE symptoms of schizophrenia (eg, hallucinations).
  • Note that the pathophysiology of schizophrenia is likely far more complicated that this.

Nigrostriatal Pathway

  • Ventral tegmental area projects to the striatum (caudate and putamen) in the center.
  • It is responsible for movement.
  • Extrapyramidal side effects from antipsychotics stem from their impact on this dopaminergic pathway – this will be a key topic in this tutorial.

Tuberoinfundibular Pathway

  • Involves the anterior hypothalamus and pituitary gland.
  • The paraventricular and arcuate (aka infundibular) nuclei project to the pituitary gland, specifically the median eminence.
  • This region is responsible for prolactin release, which is under tonic inhibition by dopamine.
  • Thus, when psychotropic agents inhibit dopamine, they disinhibit prolactin release, which results in hyperprolactinemia.
    • Hyperprolactinemia has side effects of amenorrhea-galactorrhea (a lack of menses and inappropriate milky discharge from the nipples), along with other side effects we'll address later.

Antipsychotic Side Effects

As with many different pharmacologic classes of agents, our choice of agent is less dependent upon efficacy (so many of the agents have such similar efficacy) and more related to the potential side effects.

We can think about these effects based on the receptor being inhibited and the organ system that is impacted.

extrapyramidal side effects

  • Extrapyramidal side effects encompass both hypokinetic and hyperkinetic movements. They are most prominent with the typical antipsychotics, as they have biggest relative impact on dopamine.

Hypokinetic Movements: Parkinsonism

Parkinsonism

  • We can think of the hypokinetic side under the umbrella term: parkinsonism (which is the prominent feature of Parkinson's disease), and show key signs – pseudodepression, a flattening of affect, and akinesia, a rigidity of movement observed in parkinsonian gait.
    • Pseudodepression refers to the appearance of depression, because of the flattening of affect, but it is not mood-related, rather motor related.
    • Be aware that depression, itself, is an important but separate feature of Parkinson's disease.

Parkinsonian sensitivity

  • Parkinsonian patients are particularly prone to EPS symptoms, so we should absolutely avoid the typical antipsychotic agents in this patient population.
    • As an important, common clinical scenario haloperidol (Haldol) is a major offender of extrapyramidal side effects but is still widely used on an as needed basis for psychosis in hospitalized patients.
    • Parkinsonian patients are particularly sensitive to its potential for dopamine inhibition and can suffer greatly from its administration.

Dopamine / acetylcholine balance

  • Benztropine is a muscarinic acetylcholine receptor antagonist, which helps prevent hypokinetic effects in PD when there is excessive dopamine (DA) blockade (it also is used to treat acute dystonia (see below)).
  • Movement involves a delicate balance between activation of dopamine and acetylcholine.
    • Dopamine excites movement and acetylcholine inhibits it.
    • Thus, dopamine blockade reduces movement and acetylcholine blockade stimulates it.
    • We use amantadine, in addition to benztropine, to help treat EPS.
    • Pimavanserin is a selective serotonin inverse agonist introduced for the treatment of psychosis in Parkinson's disease to try to prevent psychosis without worsening the parkinsonism through dopamine inhibition.

Hyperkinetic Movements

Choreoathetoid movements

  • For hyperkinetic movement side effects, think choreoathetoid movements (think of Huntington's disease: chorea – jerking movements, athetosis – slow, writhing movements), and show dystonic posturing (eg, torticollis).
  • Why should chronic dopamine inhibition cause excess movement when we just learned that dopamine inhibition reduces movement?
    • Because dopamine receptor densities and sensitivities are dynamic and will up and downregulate depending on chronic synaptic dopamine levels amongst other factors.

Tardive dyskinesia

  • Tardive dyskinesia is a disorder with prominent involuntary buccal and facial movements (chewing, grimacing, tongue protrusion, lip smacking and fish-like puckering, rapid eye blinking) and less common limb and trunk choreoathetoid movements (jerking and twisting) can result from chronic dopamine (DA) blockade.
  • Management of tardive dyskinesia can include any of the following:
    • Switch from a typical to an atypical antipsychotic (remember these rely less on dopamine blockade and more on serotinergic blockade to exert their effect).
    • Eliminate centrally-acting anticholinergic agents (remember: Ach reduces movement, so we want to increase ACh activity when there is excess movement).
    • Add a benzodiazepine to enhance GABAergic activity.
    • There are now two vesicular monoamine transporter 2 (VMAT2) inhibitors: valbenazine and deutetrabenazine, which are used to treat tardive dyskinesia.
    • Tetrabenazine pre-dated these drugs and was often used in practice for tardive dyskinesia, although it was officially approved for chorea in Huntington's disease.
    • Note that it's essential to reduce dopamine blockade slowly to avoid serious exacerbations.

Acute dystonic reactions

  • It's critical to know that for acute dystonic reactions, which can cause life-threating throat spasm, we want to emergently give a mAChR antagonist, so parenteral (IV formulation) benztropine is the treatment of choice.
  • Alternative treatments include diphenhydramine, which has antihistaminergic and anticholinergic properties, and is available IV formulation in some countries, or a benzodiazepine, which can reduce spasm via GABAergic activity.

Neuroleptic malignant syndrome

  • Neuroleptic malignant syndrome is a potentially life-threatening effect of antipsychotics secondary to postsynaptic dopamine receptor blockade, causing muscle damage/breakdown.
  • It manifests with elevated creatine kinase levels (a sign of muscle damage); stress-induced leukocytosis (elevated white blood cell counts (WBC)), fever, and autonomic instability. It is potentially life-threatening.
  • As part of treatment, we can try dantrolene, a muscle relaxer via ryanodine receptor 1 inhibition, or we can try to override the dopamine blockade with bromocriptine, a dopamine agonist.
    • Being a dopamine agonist, bromocriptine is used to inhibit prolactin release from prolactin-secreting pituitary tumors.

Definition of "Neuroleptic"

  • The "neuroleptic," in neuroleptic malignant syndrome generally refers to an antipsychotic with the potential for extrapyramidal side effects.
  • Thus, the older-line typical antipsychotics with strong dopamine inhibitor properties are considered neuroleptic; whereas, the newer, atypical antipsychotics that have less dopamine inhibition are not.

Autonomic Nervous System

Autonomic nervous system effects are primarily due to the antimuscarinic and antiadrenergic effects of antipsychotics.

Anticholinergic

  • Anticholinergic effects (atropine-like effects) are best remembered through the following mnemonic (which basically describes excessive sympathetic nervous system effects):
    • blind as a bat (due to the pupillary dilation and ocular accommodation impairments)
    • hot as a hare (due to increase in core body temperature)
    • mad as a hatter (delirium)
    • dry as a bone (dry mouth, dry eyes, loss of sweating)
    • red as a beet (vasodilatory flushing).
  • Although these anticholinergic SEs are common with many of the typical and atypical antipsychotics, they are less common with ziprasidone and aripiprazole, so they may be a good alternative.

Anti-adrenergic

  • Anti-adrenergic effects include postural hypotension and difficulty with ejaculation.

metabolic & endocrine

Now, the metabolic and endocrine effects, which we can primarily ascribe to dopamine and serotonin inhibition.

Anti-dopaminergic

  • First, dopamine inhibition, which, again, is most prominent with the typical antipsychotics, can result in hyperprolactinemia.
    • Hyperprolactinemia can cause amenorrhea-galactorrhea, and also can result in osteoporosis, infertility, loss of libido, and impotence.
    • Naturally, we want to switch to an antipsychotic with the least amount of anti-dopaminergic properties.
    • It's important to remember that risperidone is an atypical antipsychotic that still has significant antidopaminergic properties, so it would not be a good choice in hyperprolactinemia.

Anti-serotinergic

  • Anti-serotinergic effects result in weight gain; hyperglycemia; and hyperlipidemia.
  • The atypical antipsychotics with the highest likelihood of producing these effects are clozapine and olanzapine.

Cardiac Conduction

Cardiac dysrhythmias

  • Cardiac dysrhythmias are namely QT prolongation and related consequences.
    • Single-out the following key culprits: thioridazine, droperidol (an antiemetic), as well as some of the atypicals: especially ziprasidone and quetiapine.
  • Note, however, that the clinical significance of the QT prolongation from the atypicals remains in question.

idiosyncratic reactions

Now, let's address a couple of important idiosyncratic reactions:

Clozapine: agranulocytosis

  • Clozapine can cause agranulocytosis, a potentially lethal reduction in white blood cells (namely neutrophils), so frequent CBCs need to be checked: weekly CBC's for at least the first six months.
  • It was discovered to be a highly effect atypical antipsychotic that does not inhibit D2 receptors (but does inhibit D4 receptors) and exerts its greatest effect via serotinergic and adrenergic inhibition.
  • It was banned for many years (in the 1970s and 1980s) because of the potential for agranulocytosis.

Thioridazine: retinitis pigmentosa

  • Next, indicate that thioridazine can cause retinal deposits, which can result in retinitis pigmentosa.

Lithium

Lastly, let's learn about lithium.

Mechanism of Action

Numerous Actions

  • Lithium acts at many neurophysiological levels, including on neurotransmitters such as dopamine, serotonin, GABA, and NMDA, and it acts on second messenger systems, such as adenylate cyclase and the phosphoinositide cycle.

Inositol depletion hypothesis

We focus on this last mechanism, called the inositol depletion hypothesis, because it is putatively considered to be the most important.

  • Lithium blocks the conversion of IP2 (inositol diphosphate) to IP1 (inositol monophosphate).
  • And it blocks the conversion of IP1 to inositol.
  • These are key steps in neuronal membrane inositol recycling.
    • Specifically, it blocks inositol monophosphatase (IMPase) and inositol poliphosphatase (IPPase).
    • This inhibition of inositol recycling results in a reduction of calcium release, diacylglycerol (DAG) activation, and protein kinase C activity.

Target Concentration (Narrow Window)

Target Concentration

  • Indicate that the target therapeutic concentration is 0.6 to 1.2 mEq/L, which is a narrow therapeutic window – it's easy for patients to become toxic or subtherapeutic.

Renally Excreted

Draw a kidney because lithium is renally excreted.

  • DECREASE Renal Clearance (lead to lithium toxicity)
    • The following can DECREASE renal clearance and produce lithium toxicity: volume depletion, NSAIDs, and various diuretics: thiazides, angiotensin-converting enzyme inhibitors (ACEIs), and loop diuretics.
  • INCREASE Renal Clearance (lead to subtherapeutic lithium levels)
    • On the other end of the spectrum the following can INCREASE renal clearance and produce subtherapeutic levels: xanthines (caffeine and theophylline); increases in salt intake; pregnancy; dialysis – note that dialysis is used to treat lithium toxicity

Side Effects

Lithium is also known to impact additional systems that affect various physiologic processes including glucose metabolism; ADH secretion; thyroid hormones; and the hypothalamic-pituitary-adrenal axis, which leads us to some of the key side effects of lithium.

The following are important potential side effects:

  • Coarse tremor is common even at therapeutic doses.
  • At toxic doses, hyperreflexia, nystagmus, ataxia and confusion can occur.
  • Decrease in thyroid function – there's the potential for goiter (thyroid enlargement) but rarely clinical hypothyroidism.
  • Nephrogenic diabetes insipidus, manifesting with polydipsia and polyuria.
  • Edema.
  • Cardiac conduction defects – these are generally mild.
  • Teratogenicity exists but the risk of congenital cardiac defects (Ebstein anomaly) is controversial.
  • Other common symptoms include: leukocytosis, acne, folliculitis.

Antipsychotic Agents

Typical Antipsychotics

Selection of Typical Antipsychotics

  • Phenothiazines:
    • (low-potency) - chlorpromazine, thioridazine.
    • (medium/high-potency) - perphenazine (a mid-potency piperazine that is notable for being found in the CATIE trial to be comparable to (but less expensive than) the atypicals).
  • Thioxanthene:
    • (medium-potency) - thiothixene
  • Butyrophenone:
    • (high-potency) - haloperidol (the most widely-used typical antipsychotic)

Atypical Antipsychotics

Selection of Atypical Antipsychotics (from US FDA)

  • Aripiprazole (marketed as Abilify)
  • Asenapine Maleate (marketed as Saphris)
  • Clozapine (marketed as Clozaril)
  • Iloperidone (marketed as Fanapt)
  • Lurasidone (marketed as Latuda)
  • Olanzapine (marketed as Zyprexa)
  • Olanzapine/Fluoxetine (marketed as Symbyax)
  • Paliperidone (marketed as Invega)
  • Quetiapine (marketed as Seroquel)
  • Risperidone (marketed as Risperdal)
  • Ziprasidone (marketed as Geodon)

References

  • Alda, Martin. "LITHIUM IN THE TREATMENT OF BIPOLAR DISORDER: PHARMACOLOGY AND PHARMACOGENETICS." Molecular Psychiatry 20, no. 6 (June 2015): 661–70. https://doi.org/10.1038/mp.2015.4.
  • Caroff, Stanley N., Saurabh Aggarwal, and Charles Yonan. "Treatment of Tardive Dyskinesia with Tetrabenazine or Valbenazine: A Systematic Review." Journal of Comparative Effectiveness Research 7, no. 2 (February 2018): 135–48. https://doi.org/10.2217/cer-2017-0065.
  • "Cholinesterase Inhibitors: Tremor and Exacerbation of Parkinson's Disease." Prescrire International 16, no. 91 (October 2007): 197–98.
  • Christian, Robert, Lissette Saavedra, Bradley N. Gaynes, Brian Sheitman, Roberta CM Wines, Daniel E. Jonas, Meera Viswanathan, Alan R. Ellis, Carol Woodell, and Timothy S. Carey. Tables of FDA-Approved Indications for First- and Second-Generation Antipsychotics. Future Research Needs for First- and Second-Generation Antipsychotics for Children and Young Adults [Internet]. Agency for Healthcare Research and Quality (US), 2012. https://www.ncbi.nlm.nih.gov/books/NBK84656/.
  • Hartman, Leah I., R. Walter Heinrichs, and Farzaneh Mashhadi. "The Continuing Story of Schizophrenia and Schizoaffective Disorder: One Condition or Two?" Schizophrenia Research: Cognition 16 (February 10, 2019): 36–42. https://doi.org/10.1016/j.scog.2019.01.001.
  • Katzung, Bertram G. Basic and Clinical Pharmacology 14th Edition. McGraw Hill Professional, 2017.
  • Lester, Deranda B., Tiffany D. Rogers, and Charles D. Blaha. "Acetylcholine–Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders." CNS Neuroscience & Therapeutics 16, no. 3 (2010): 137–62. https://doi.org/10.1111/j.1755-5949.2010.00142.x.
  • Meltzer, HY, and BW Massey. "The Role of Serotonin Receptors in the Action of Atypical Antipsychotic Drugs." Current Opinion in Pharmacology, Neurosciences, 11, no. 1 (February 1, 2011): 59–67. https://doi.org/10.1016/j.coph.2011.02.007.
  • Onofrj, Marco, and Astrid Thomas. "Which Motor Symptoms Worsen during Cholinesterase Treatment," February 11, 2021. https://n.neurology.org/content/which-motor-symptoms-worsen-during-cholinesterase-treatment.
  • Rizzi, Giorgio, and Kelly R. Tan. "Dopamine and Acetylcholine, a Circuit Point of View in Parkinson's Disease." Frontiers in Neural Circuits 11 (2017). https://doi.org/10.3389/fncir.2017.00110.
  • Trevor, Anthony J., Bertram G. Katzung, and Marieke Knuidering-Hall. Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition. McGraw Hill Professional, 2018.