Table of Contents
What is Dementia?
Dementia, or neurocognitive disorder, is a nonspecific term referring to a syndrome consisting of memory and cognitive impairment. Typically, these impairments are slow and progress over time although some forms of dementia are very rapid in their progression. Eventually, individuals suffering from dementia require assistance with everyday needs. Common symptoms of dementia include
- Memory problems
- Personality changes
- Mood changes
- Language problems
- Perceptual changes
- Decision-making problems and other Executive dysfunctions (attention, organization, problem solving, planning)
In most cases, the first sign of dementia is short term memory loss or forgetfulness. However, it is important to note that numerous neuropsychiatric disorders and medical problems are associated with memory issues. Depression, Anxiety, Anemia, ADHD, and sleep deprivation are just a few of the many disorders associated with forgetfulness.
Types of Dementia
The term “dementia” or “neurocognitive disorder” is an umbrella term that includes many different types. In 2015, an estimated 47 million people worldwide suffer from dementia. The most common types of dementia are described below:
Alzheimer’s Disease (AD)
Alzheimer’s disease (AD) is the most common type of dementia (60-80% of cases) and is considered a “cortical” dementia. That is, AD is characterized by impairment of the association cortices, which are areas of the cortex responsible for the integration and processing of information from primary sensory cortical areas. For example, the parietal association cortex has a major role in attending to stimuli in the external and internal environments, the temporal association cortex as an important role in the identification of stimuli, and the frontal association cortex plays an important role in planning appropriate responses (such as behaviors). In addition to cortical degeneration, other areas of the brain are also affected in AD, with memory loss reflecting hippocampal involvement and affective (mood) changes reflecting limbic system involvement.
Neurocognitive Disorder (NCD) due to Alzheimer’s disease is a clinical diagnosis and can be definitively diagnosed only by postmortem direct visualization of the brain. When diagnosing “Mild” or “Major” Neurocognitive disorder due to Alzheimer’s disease, the onset must be slow, and symptoms must progress gradually. “Possible” Alzheimer’s disease is indicated if there is no evidence of contributing genetic mutation, while “Probable” Alzheimer’s is diagnosed with confirmed with genetic testing.
Patients and caregivers may notice that tasks that used to be relatively easy are now more difficult, particularly more complex cognitive tasks. Anhedonia (loss of enjoyment of previously pleasurable things) is also common. Some anomia or anomic aphasia may be experienced, in which the ability to name familiar objects or people is impaired. Additionally, problems with misplacing or not finding items or getting lost on familiar routes occur with increasing frequency.
As the disease progresses, these issues get worse, and other behavioral and cognitive changes occur. Changes in physiological processes, such as disrupted sleep, incontinence, and difficulty swallowing, are seen. Psychiatric symptoms such as delusions, hallucinations, depressed mood, and agitation (including violent outbursts) may occur. Tasks that allow for basic self-sufficiency may suffer, including the ability to prepare food, to choose appropriate clothing, and, particularly, to drive. Additionally, the person’s ability to recognize danger and to accurately and appropriately judge a situation is diminished. Reading and writing become more difficult, and strategies such as leaving lists and notes as memory cues may become less effective. Verbal communication also suffers as the disease progresses, and language becomes confused, with incorrect word usage and mispronunciation of words. Much of our sense of “self” comes from our memory and cognitive function, and this commonly is lost in those with advancing AD. The loss of personal episodic memories contributes to this. With loss of these functions comes withdrawal from social contact with family and friends. AD will eventually take away completely the ability to use language, interact with or even recognize family or friends, and live independently.
For additional information, visit the Alzheimer’s Association website at www.alz.org.
Amyloid Plaques and Neurofibrillary Tangles
Amyloid plaques and neurofibrillary tangles are the classic pathological findings in the brain of patients with AD. These plaques and tangles cause degeneration of cells throughout the cortex, especially the frontotemporal association cortex. In addition, up to 45% of synapses are lost as the disease progresses and likely explains the significant cognitive impairment that occurs over time in AD.
FIGURE ABOVE: Pathological changes in the brain with advanced Alzheimer’s disease (AD) The brain of an individual with AD is compared with a healthy brain from an age-matched individual. The brain of the individual with AD shows significant atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. (Courtesy of Ann C. McKee, MD, Boston University School of Medicine/VA Boston Healthcare System.)
Amyloid plaques are the result of the accumulation of the beta amyloid protein (β-amyloid/A-beta [Aβ]) between neurons. Aβ is a protein fragment normally produced by the brain by enzymatic cleavage of amyloid precursor protein (APP). APP undegoes numerous cleavages (see figure below) to eventually produce either the 40-amino- acid (Aβ40) or the 42-amino-acid (Aβ42) form of Aβ.
Fragments of APP have important roles in kinase activation, facilitation of gene transcription, cholesterol transport regulation, and pro-inflammatory/antimicrobial activities. Normally, these fragments undergo degradation and removal. However, in the brains of those with AD, these protein fragments, particularly Aβ42, accumulate to form plaques. Several different subtypes of plaques exist. Three common types include:
- Senile or neuritic plaque has a core of the amyloid protein surrounded by abnormal dendrites or axons. Microglial cells or reactive astrocytes are found in the periphery of many of these plaques.
- Focal diffuse deposits of amyloid with no neurites surrounding the core
- A dense core of amyloid without neurites. The plaques are considered the long-term outcome of neuritic plaques after the surrounding axons and dendrites have died.
Neurofibrillary tangles (NFTs) are fibrous inclusions that are abnormally located in the cytoplasm of neurons. The neurons particularly susceptible to NFTs are pyramidal neurons—those with a pyramid-shaped cell body. The primary component of these tangles is the protein tau, which is a protein associated with microtubules, which are long filaments that help maintain cellular structure and provide a “highway” for axonal transport. As a component of these tangles, the tau is abnormally phosphorylated. Other proteins, including ubiquitin, are also found in NFTs.
In early stages of the disease, NFTs are found in the entorhinal cortex, with progression to the hippocampus and neocortex as the disease process continues. Additionally, neurons in the basal forebrain cholinergic and monoaminergic systems are susceptible to damage by AD pathological processes.
Below is a PET scan comparing healthy brain and AD-affected brain. One of several new methods for visualizing amyloid plaques in living brains, Pittsburgh compound B (PiB) dye accumulates in the plaques and can be visualized using PET scanning. Presence of these plaques is more common in those individuals with Alzheimer’s or significant cognitive impairment. (From Wolk et al., 2009).
Major Risk Factors
- Advancing age
- Family history of dementia or AD
- Untreated hypertension
- High cholesterol
- Sedentary lifestyle
- History of head trauma or hypoxic brain injury
- Bipolar disorder
- Post-traumatic stress disorder (PTSD)
Genetic contributors to AD consist of risk genes and deterministic genes. Deterministic genes are those that can directly cause disease.
Three deterministic genes are known to directly cause autosomal dominant Alzheimer’s disease (ADAD):
- APP, found on chromosome 21
- Presenilin-1 (PS-1) on chromosome 14
- Presenilin-2 (PS-2) on chromosome 1
In ADAD, symptom onset is likely to occur before age 60 (it can occur as early as the 30s). Although ADAD is of concern, only about 5% of AD cases are familial.
The risk gene with the greatest influence on disease development is the gene for apolipoprotein E (ApoE). ApoE is normally a component of very-low-density lipoproteins (VLDLs). These lipoproteins remove excess cholesterol from the blood and carry it to the liver for degradation. The presence of the gene for the E4 form of this (APOEe4) increases risk; inheritance of this form from both parents increases risk further and may lead to earlier onset of the disease.
Down Syndrome and Alzheimer’s Disease
AD is closely linked to trisomy 21 (Down Syndrome). By the age of 30 to 40, most patients with Down syndrome will develop the plaques and tangles that are associated with AD. These changes are nearly universal among patients with Down syndrome who reach this age, and although the severity of plaque and tangle accumulation mimics that found in AD, not all such individuals will develop AD. One of the possibilities for the connection is that patients have three copies of the APP gene, which is located on chromosome 21.
Management of Alzheimer’s Disease
Nonpharmacological interventions are essential, effective, and first-line recommendations in the management of AD.
Nonpharmacological interventions include
- Hearing Aids, if necessary
- Keep prescription glasses updated and available at all times
- Be sure home is safe and remove anything that might cause falls (e.g, rugs, slippery mats, etc)
- Be sure bathroom has seat in shower and provide assistance to prevent falls
- Well balanced meals with appropriate caloric intake and hydration with fluids (both water and fluids with electrolytes)
- At least 25-30min of very mild physical activity with assistance (walking around the house, going outside for a short walk)
- Minimize daytime naps
- Keep lights on during the day and window shades open during the day and lights off at bedtime
- Keep mentally stimulated during the day by doing puzzles, crosswords, coloring, reading, etc
- Sleep hygiene techniques: No bright screens before bedtime, no TV in bed, minimize caffeine, make a consistent sleep schedule and/or routine.
- Minimize the use of alcohol and other substances as these can have negative effects on mood and cognition
While there are no medications to date that have reliably reversed or prevented AD, there are medications that may slow down progression of the disease.
Pharmacological interventions are presented in the table below:
|Drug||Mechanism of Action||Dosing||Indications||Contraindications|
|Donepezil (Aricept)||Acetylcholinesterase Inhibitor||5mg once daily. Increase to 10mg once daily after 4-6 weeks.||Mild-Moderate AD||Breastfeeding|
|Galantamine (Reminyl)||Acetylcholinesterase Inhibitor and Nictoine receptor agonist.||4mg twice daily. Increase to 8mg twice daily after 4 weeks. Not to exceed 12mg twice daily||Mild-Moderate AD||Renally impaired patients (if Cr Cl <9ml/min)|
|Rivastigmine (Exelon)||Acetylcholinesterase Inhibitor and Butyrylcholinesterase Inhibitor||1.5mg twice daily. Increase dose by 1.5mg twice daily at two week intervals. Not to exceed 6mg twice daily||Mild-Moderate AD||Active gastrointestinal bleeding|
|Tacrine (Cognex)||Acetylcholinesterase Inhibitor||10-20mg 2 to 3 time daily. Not to exceed 160mg/day.||Mild-Moderate AD||Hepatic impairmet, Breast Feeding|
|Memantine (Ebixa)||NMDA Receptor Non-competitive antagonist||5mg once daily. Increase by 5mg daily every week to maintenance dose of 10mg twice daily. Extended Release starts at 7mg once daily and increased by 7mg daily each week to target dose of 28mg daily.||Moderate-Severe AD||Severe Renal Impairment|
- Alzheimer’s disease is a dementia disorder that affects increasing numbers of people in the United States
- The onset of AD is preceded by neurocognitive disorder (NCD), but not all cases of NCD develop into AD.
- Early symptoms of AD include forgetfulness and impairment in other cognitive functions, including language, thinking, and judgment. Physiological changes include difficulty swallowing and disrupted sleep. Psychiatric difficulties come in the form of delusions, hallucinations, depression, and agitation.
- As the disease progresses, communication becomes increasingly difficult because of reading, writing, and verbal communication problems.
- Two pathological findings hallmark disease progression in AD: amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are formed by accumulation of AB (primarily AB42) after production by secretase cutting of the amyloid precursor protein (APP). NFTs are composed primarily of abnormally phosphorylated tau, a microtubule-associated protein, and other proteins like ubiquitin. Accumulation of NFTs results in disruption of cellular processes and eventually apoptotic cell death.
- Risk factors for development of AD include advancing age and poor cardiovascular health. Previous head injury or psychopathology can also increase risk. Several genes are associated with the development of autosomal dominant Alzheimer’s disease (ADAD) and include the genes for APP, presenilin-1, and presenilin-2. Several other genes impart increased risk for AD, including the APOEe4 allele, A2M, UBQLN1, and SORL1.
- Because of the location of risk genes on chromosome 21, AD has a strong association with Down syndrome (trisomy 21).
- AD generally is not diagnosed until after death, although newer imaging technologies may allow earlier diagnosis in the future.
- Current treatments for AD are primarily cholinesterase inhibitors and NMDA receptor modulators.
- Research indicates that AB antibodies, chemotherapy drugs, and perhaps even antibiotics may be effective treatments that will become available in the future.
Vascular dementia accounts for 20–30% of dementias and is often occurs with AD. Vascular dementia can be caused by stroke, heart attacks or any ischemic event that disrupts normal blood flow to the brain or within it. The impaired blood flow leads to cellular death and damage to brain tissue due to lack of oxygen and nutrients.
Symptoms depend on the areas of the brain most affected. Most common symptoms include
- Slowed reaction time
- Poor concentration
- Poor decision making
- Memory impairment
- Ambulation/motor problems
- Personality changes
Individuals with vascular dementia usually remain functionally stable for a period of time and then suddenly decline in a step-like manner (see graph below).
Fronto-Temporal Dementia (FTD)
Fronto-Temporal Dementia (FTD) accounts for 5–10% of patients with dementia and, as the name implies, is characterized by progressive damage to the frontal and/or temporal lobes of the cortex. The symptoms are variable depending on the frontal and temporal cortical areas that are affected, but patients often display the following symptoms:
- Changes in personality: Loss of inhibitory behaviors, socially unacceptable behaviors, aggressiveness
- Mood changes: Marked lack of empathy with others and mood swings
- Language problems: Difficulties in finding the correct word to describe something with prominent circumlocution, which is using many words to try and explain something. Also deficits in spontaneous speech.
- Memory problems: Usually memory deficits occur later in the progression of the condition.
FTD is genetically linked in about 30–50% of cases. The gene for tau protein (discussed above) is most commonly affected. The treatment of FTD is symptomatic and, at present, there is no cure or means of slowing down its progression.
Dementia with Lewy Bodies (DLB)
Dementia with Lewy Bodies (DLB) is also referred to as Lewy Body Dementia. DLB accounts for about 3–5% of dementias and is caused by the presence of Lewy Bodies (LBs) in the cortex. Recall that Lewy Bodies are protein aggregates containing the protein 𝛼-synuclein and are implicated in the pathophysiology of Parkinson’s Disease. However, patients with DLB do not necessarily have PD, although some patients may have both conditions. The symptoms of DLB are similar to that of AD but patients tend to have more visual and auditory hallucinations. Currently there is no cure for DLB and the treatment is symptomatic. However, recent clinical trials have suggested that the drugs used in the treatment of Alzheimer’s disease (acetylcholinesterase inhibitors and glutamate receptor antagonists) may be beneficial in alleviating some of the memory and cognitive problems.
Wernicke-Korsakoff Syndrome (WKS)
Korsakoff’s Syndrome (KS) is usually due to excessive intake of alcohol over a prolonged period and is due to thiamine (vitamin B1) deficiency due to poor diet and the ability of alcohol to impede the conversion of thiamine into thiamine pyrophosphate, which is its active form. The symptoms include memory loss, denial that there are any difficulties with memory, problems in acquiring new information and skills, personality changes and inventing convincing stories to fill in gaps in their memories (confabulation). The lack of thiamine causes damage to the mammillary bodies located in the posterior hypothalamus by an unknown mechanism of action. The mammillary bodies are connected to the hippocampal formation in the medial temporal lobe and damage to this area can compromise the consolidation of STMs into LTMs. Treatment includes withdrawal and abstinence from alcohol and administration of high doses of thiamine.
Parkinson’s Disease Dementia (PDD)
Parkinson’s Disease Dementia (PDD) has been reported in about 30–35% of patients with PD. Parkinson’s Disease is discussed below.
Parkinson Disease (PD)
In the early 1800s James Parkinson described a condition he called “paralysis agitans” in his famous essay “Essay on the shaking palsy.” Parkinson believed dysfunction within the medulla of the brain stem accounted for the symptoms and hypothesized that the cerebral cortex was not involved (largely based on his observations that individuals with the condition showed little to no cognitive impairment). We now know, thanks to Jean Martin Charcot and others who were studying the condition, that Parkinson Disease does involved cerebral cortical pathology. 55-60 million people are affected with Parkinson Disease worldwide, and this number will continue to climb as life expectancy increases and the world population ages. Idiopathic Parkinson’s Disease, Familial Early Onset PD, and Juvenile Onset PD make up the majority of cases. Women are much less likely to develop PD, possibly due to the protective effects of estrogen.
The classic motor symptoms of PD include:
(1) Pill Rolling Tremor. Tremors occur due to rhythmic contractions of opposing muscle groups. In PD, the tremor typically occurs at a frequency of 3-5 muscle contraction cycles per second (Hz). The tremor occurs at rest, usually starts unilaterally in the hands and fingers, and diminishes during voluntary movement and sleep. As the disease progresses, the tremor becomes more prominent, bilateral, and eventually rigidity develops.
(2) Bradykinesia or hypokinesia (slowed movement). Patients with PD are slow in their movements, have difficulty with fine motor control, and experience problems writing and/or using their hands to play instruments or type on a computer keyboard. Spontaneous movements and associated movements are diminished. When we talk to others, we use facial gestures and hand movements to express our emotions; this requires spontaneous movement. When we walk, we swing our arms and move our legs in a specific way to keep our balance; this requires associated movements. When we feel thirsty while reading this lesson, we may reach for our cup of coffee (or water, or wine); this requires initiation of movement. All of these are affected in patient’s with PD which leads to the classic findings of “masked-like” facial expressions, minimal arm swing/shuffling gait, and delayed initiation of voluntary movement.
(3) Rigidity (Cogwheel Rigidity). When apposing muscle groups are contracting at the same time or are always in a contracted state, this leads to muscle rigidity. When you try to move the arms of an individual with PD, you will find it difficult. There is a passive resistance to movement similar to the negativism or waxy flexibility seen in catatonia.
(4) Posture problems. Standing or sitting up straight requires the axial/postural muscles. Patient’s with PD have difficulty maintaining appropriate posture and are seen stooped or hunched over.
The classic “non-motor” symptoms of PD include:
(1) Cognitive deficits. Dementia and memory problems often precede motor symptoms of PD. The cognitive deficits seen in patients with PD are thought to be a result of damage to the cholinergic system (especially the nucleus basalis of meynert) and build up of insoluble protein aggregates within cortical and sub-cortical structures.
(2) Constipation. Likely related to cholinergic dysfunction.
(3) Olfactory deficits. Diminished sense of smell may occur before motor symptoms.
(4) Autonomic Dysfunction. Disrupted sympathetic innervation to the heart and other important organs may lead to bradycardia and hypotension, urinary retention, postural hypotension, sweating, and drooling.
(5) Rapid Eye Movement Sleep Behavior Disorder (RBD). During sleep, patients with PD may “act out” their dreams. As will be discussed in a later lesson, REM sleep is normally a stage of sleep characterized by muscle paralysis. RBD occurs when paralysis of muscles does not occur and patient’s move around while dreaming.
(6) Mood and personality changes. Depression, apathy, anxiety, irritability, agitation, and psychosis often occur in patients with PD–likely related to destruction of serotonergic projections from the raphe nucleus, noradrenergic projections from the locus coeruleus, cholinergic neurons, dopaminergic projections from the ventral tegmental area, and glutamatergic/GABAergic neurons.
The Motor System: A Brief Review
The two main motor tracts that control skeletal muscles for movement originate in the motor cortex of the brain and are called the corticospinal tract (or pyramidal tract) and the corticobulbar tract. The corticospinal tract starts in the motor cortex and many, but not all, of the neuronal fibers cross over (or decussate) at the medullary pyramids to eventually synapse on lower motor neurons in the contralateral anterior horn of the spinal cord. Therefore, the right motor cortex primarily controls the left side of the body. Similarly, the corticobulbar tract originates in the motor cortex and many, but not all, of the neuronal fibers cross over and synapses on lower motor neurons in the brain stem. Therefore, the right motor cortex primarily controls movement of the muscles on the left side of the body.
Descending Motor Pathways
The execution of motor movements involves more than just these two tracts. Information from the cortex and subcortical areas are integrated and processed and eventually transmitted to the motor cortex to execute movement. We call these motor “coordination/integration” pathways in the brain “extra pyramidal” because they occur outside of the traditional corticospinal/corticobulbar (pyramidal) motor tracts. The structures that make up the Extrapyramidal motor system include the Basal Ganglia, the Substantia Nigra (in the midbrain), and the subthalamic nucleus.
Extrapyramidal Motor System
The structures that make up the Extrapyramidal motor system include the Basal Ganglia, the Substantia Nigra (in the midbrain), and the subthalamic nucleus. Basal Ganglia, as discussed in the Anatomy sections, include the caudate nucleus, the putamen nucleus, and the globus pallidus. The caudate nucleus and the putamen nucleus are called the “striatum” or “neostriatum” whereas the three nuclei together are referred to as the “corpus striatum.” The globus pallidus is divided into two parts, the internal and external parts. The substantia nigra (SN) is located in the midbrain and is named after the black pigmented neuronal cell bodies seen on anatomical sections. The SN is divided into two parts, the pars reticulata (SNr) and the pars compacta (SNc) Neuronal inputs to the striatum come from the motor cortex, substantia nigra pars compacta, the thalamus, and subcortical structures like the dorsal raphe nucleus. Information is processed in the striatum and eventually sent to the thalamic nuclei and back to the motor cortex. But from the striatum to the thalamic nuclei, neurons first synapse at the the globus pallidus internal (GPi) and substantia nigra pars reticulata (SNr). From the GPi/SNr, neuronal signals are sent to the thalamic nuclei. To make things more complicated, some of the neurons from the striatum don’t directly synapse on the GPi/SNr and instead take a detour at the globus pallidus external (GPe) and subthalamic nucleus (STN).
The extrapyramidal system and the motor nuclei of the thalamus form a loop that obtains information from the cortex and other areas of the brain, integrates and processes it, and relays it back to the motor cortex to modulate motor activity in the corticospinal and corticobulbar tracts. The diagrams can give you a headache but the simple concept is that stimulation of the direct pathway leads to activation of the motor cortex. On the other hand, stimulation of the indirect pathway decreases activation of the motor cortex (“indirect pathway inhibits”). This occurs through a series of glutamatergic and gabaergic connections. Please note that the diagrams are overly simplistic and do not show many of the other neurotransmitters involved (substance P, opioid peptides, neurokinin, etc).
Dopamine (DA) modulates this circuit. Stimulation of D1 receptors in the striatum by dopamine stimulates the direct pathway and increases motor cortex activity. Stimulation of D2 receptors in the striatum inhibits the indirect pathway. Therefore, the overall effect of dopamine is to increase activity at the motor cortex. Loss of dopamine input from the SNc (as seen in Parkinson’s Disease) or blockade of dopamine receptors via medications (like antipsychotics) will decrease activity in the motor cortex and cause slowed movements.
Acetylcholine (ACh) has the opposite effect of DA. Stimulation of M2 receptors in the indirect pathway stimulates the indirect pathway whereas stimulation of M1 receptors in the direct pathway inhibit the direct pathway. This leads to an overall net effect of decreased activity at the motor cortex. Note that ACh interneurons are activated by the glutamate neurons from the motor cortex but are normally under inhibitory control by DA from the nigrostriatal tract. This is why we give anticholinergic medications like benztropine (cogentin) to help with extrapyramidal symptoms (EPS) and/or the slowed movements associated with Parkinson Disease.
Dopamine does not readily cross the blood brain barrier. However, its precursor, L-Dopa, does. The mainstay treatment for Parkinson’s disease is “dopamine replacement” with L-Dopa. Because L-Dopa is vulnerable to enzymatic degradation (via monoamine oxidases/MAOs, Catechol-O-Methyl transferases/COMTs, and aromatic amino acid decarboxylases/AADCs) within the intestine, L-Dopa is often administered with blockers of these enzymes (e.g. carbidopa) to ensure L-dopa reaches the brain. Despite the presence of inhibitors of these enzymes, therapeutic doses of L-Dopa still have some conversion to dopamine and norepinephrine in the periphery. This may explain the side effects seen with L-Dopa treatment.
Side effects of L-Dopa are thought to result from the conversion of L-Dopa to dopamine, norepinephrine, and/or epinephrine in the periphery. Dopamine in the medulla stimulates the chemoreceptor trigger zone to cause nausea/vomiting and dopamine alters gastrointestinal smooth muscle activity leading to gastrointestinal side effects. The conversion of L-Dopa to norepinephrine in the periphery can lead to sympathetic activation of the heart (tachycardia) and other cardiac arrhythmias. Neuropsychiatric symptoms such as depression, anxiety, agitation, aggression, impulsivity problems (gambling, spending) and psychosis (hallucinations and paranoia) can occur as side effects of L-Dopa treatment.
- J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
- Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
- McCarron, Robert M., et al. Lippincotts Primary Care Psychiatry: for Primary Care Clinicians and Trainees, Medical Specialists, Neurologists, Emergency Medical Professionals, Mental Health Providers, and Trainees. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009.
- Focus Psychiatry Review, Dsm-5: Dsm-5 Revised Edition by Deborah J. Hales (Author, Editor), Mark Hyman Rapaport (Author, Editor)
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC.
- Arciniegas, Yudofsky, Hales (editors). The American Psychiatric Association Publishing Textbook Of Neuropsychiatry And Clinical Neurosciences. Sixth Edition.
- Bear, Mark F.,, Barry W. Connors, and Michael A. Paradiso. Neuroscience: Exploring the Brain. Fourth edition. Philadelphia: Wolters Kluwer, 2016.
- Blumenfeld, Hal. Neuroanatomy Through Clinical Cases. 2nd ed. Sunderland, Mass.: Sinauer Associates, 2010.
- Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
- Higgins, E. S., & George, M. S. (2019). The neuroscience of clinical psychiatry: the pathophysiology of behavior and mental illness. Philadelphia: Wolters Kluwer.
- Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
- Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
- Mendez, M. F., Clark, D. L., Boutros, N. N. (2018). The Brain and Behavior: An Introduction to Behavioral Neuroanatomy. United States: Cambridge University Press.
- Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
- Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
- Neuroscience, Sixth Edition. Dale Purves, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, Richard D. Mooney, Michael L. Platt, and Leonard E. White. Oxford University Press. 2018.
- Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
- Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
- Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
- Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th
- Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st 2012. APP.
- Benjamin J. Sadock, Virginia A. Sadock. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia :Lippincott Williams & Wilkins, 2000.
- Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
- Stein, Lerer, and Stahl. Essential Evidence-Based Psychopharmacology. Second Edition. 2012.
- Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
- Meyer, Jerrold, and Quenzer, Linda. Psychopharmacology: Drugs, the Brain, and Behavior. Sinauer Associates. 2018.