A comprehensive review introduction


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Table 18: Stimulant medications and their notable side effects (138).

A community based study conducted by the Department of Pediatrics, School of Medicine at Yale found that MPH have growth suppression factors, with children taking the drug at doses 10-80 mg/day exhibiting significant height differences when compared to untreated biological siblings at the same age (139).

Another ADHD medication, atomoxetine (Strattera), also carries an FDA warning. Studies show that children and adolescents with ADHD who take atomoxetine are more likely to harbor suicidal thoughts than who do not take it.

Magnesium pemoline (Cylert) is associated with hepatic failure and comes with the FDA Black Box Warning. It is not considered the first line drug for ADHD and when a clinician does plan to start a patient on it, a written informed consent should be obtained prior to initiation of therapy (140).


Cure vs. Control

Psychopharmacology, with its advances in theories and practice, still comes up short to actually addressing the root cause of mental illness. The SSRIs is a good example. Even after decades of research, the serotonin and norepinephrine hypothesis as the cause of depression is still largely controversial. This will be discussed in depth in the section, ethical dilemma, but suffice to state for now that the financial stakes are high on these hypotheses.

In the context of mental illness, psychopharmacologic interventions are only modest palliative care measures. In other words, it’s all about control of symptoms to improve the quality of life.

Psychiatry, the mother tree of psychopharmacology, is largely governed by the mission to protect public health, to the extent of creating a forceful barrier against those who pose a danger to it. The asylums and rehabilitation facilities are evidence of this endeavor. On the other hand, because public safety is the driving directive of this field, the patients that are governed by it sometimes take secondary importance. Psychoactive drugs alter antisocial behavioral tendencies, allowing mentally ill individuals to function in society. But this seemingly positive benefit comes with a price; the altered behavior makes the families and public feel safer while the patient may not necessarily feel better. For instance, schizophrenia is managed with neuroleptic medications that target its destructive symptoms such as hallucinations, delusions and thought disorders at doses that cause significant debilitating side effects such as sedation, lethargy, emotional blunting, impotence, Parkinsonism, and agitation. As a result, many patients not only skip these drugs but the entire psychiatric treatment plan altogether. Indeed, a lot of patients require legal-coercion in order to take their prescribed drugs and they are not entirely to blame. The bottom line is optimal public safety does not always equate to patient’s well being, nor are they always compatible. Either one has to give in to the other.

Since the patients are the ultimate expert in their own subjective psychiatric health, it makes sense that they take a more active role in their psychopharmacologic therapy. This type of approach is not new; the patient controlled analgesia (PCA) is proof of that. A lot of clinicians are wary of this type of approach, and their fears are warranted. Psychoactive drugs are known to cause psychological and physical dependence - potential risks that sometimes outweigh the benefits, resulting in under-dosing and needless suffering. The idea of enhancing psychological well-being to augment suffering in the name of palliative psychopharmacological treatment is still a very much debated topic to this day.

Not all psychiatric patients respond to psychoactive drugs the same way. This is why there is a need for an established plan that includes regular and frequent consultations throughout the course of treatment (usually lifetime). The pharmacotherapy tenet, “start low, go slow”, needs to be followed especially for these medications. But more than this, the challenge to the clinicians lies in the fact that it takes considerable amount of time to find the right drug for each patient and even longer to find the minimum effective dose that balances the risks and benefits (141).

Toxicity levels

According to a report published by the National Center for Health Statistics (NCHS) in 2011, the number of adolescents and adults that use antidepressants in the U.S. climbed to a staggering 400% in the last three decades. What’s more, more than 60% of them have taken it for 2 years or longer, with 14% having taken the medication for 10 years or more. But perhaps the most chilling part of this report is that less than one-third of them and less than one-half of those taking multiple antidepressants have seen a psychiatrist in the past year (142).

Perhaps the class of antidepressants that concerns clinicians the most is SSRIs because although they have lesser incidence of toxicity, they are the most widely prescribed in the U.S. Serotonin toxicity, a common adverse effect of this class, encompasses a wide range of signs and symptoms affecting the neuromuscular, autonomic, cardiovascular, nervous and gastrointestinal systems, where the highest concentrations of serotonin receptors are found. In its most severe form, it is known as serotonin syndrome and its most frequent cause is the co-administration of SSRIs with MAOIs (143) (146).

The drug interaction can occur after as little as 2 doses have been administered. It may then trigger a series of acute symptoms such as agitation, gastrointestinal disturbances, and tremor that worsen rapidly. Patients who experience milder forms may not recognize these as manifestations of toxicity and thus, not seek treatment. Aside from drug interactions, serotonin syndrome can also occur due to excessive dosage for suicide purposes, although this rarely happens (146).

The mechanisms and their precipitating factors that cause an abnormal increase in serotonin levels are (144):

  • Direct stimulation of 5HT-receptor: buspirone, triptans, lithium, carbamazepine, peyote

  • Direct release of 5HT from presynaptic storage: amphetamines, MDMA, cocaine, reserpine, levodopa, monoamine oxidase inhibitors, opioids such as codeine and pentazocine

  • Greater availability of 5HT precursors - L-tryptophan from tyramine containing foods

  • Reduced reuptake of 5HT: SSRIs, trazodone, nefazodone, venlafaxine, tricyclic antidepressants, dextromethorphan, meperidine, St. John's wort, amphetamines, carbamazepine, methadone, linezolid

  • Presence of comorbid conditions such as serotonin-secreting tumors

Citalopram has the highest fatality rate among all SSRIs (145). It exerts a dose-dependent QT prolongation resulting in the revision of the drug’s prescribing information to include it in 2011. It is contraindicated in individuals with congenital long QT syndrome, with the recommended daily dose not exceeding 40 mg (144).

Tricyclic antidepressants (TCAs), though not the first line drugs for depression, are still used in some patients. The pharmacologic mechanisms that cause TCAs toxicity are (147):

  • Norepinephrine and serotonin reuptake inhibition at nerve terminals

  • Anticholinergic activity

  • Inhibition of alpha-adrenergic receptors

  • Blockade of cardiac sodium channels in the myocardium

Among the TCAs, amitriptyline (Elavil) toxicity has the highest number of fatalities (148). Patients exhibit major cardiac toxicity symptoms when drug concentration and that of its metabolite, nortriptyline, exceed 300 ng/mL. This is most apparent with QRS widening that leads to ventricular tachycardia and asystole. Because their relative plasma levels are highly variable, toxicity can also occur at lower concentrations (149).

Monoamine oxidase inhibitors (MAOIs) are older antidepressants with well documented dietary-induced toxicity. They are last resort drugs in the treatment of resistant depression, usually reserved for cases where patients do not respond to SSRIs. They have high oral absorption with peak plasma concentrations occurring within 2-3 hours of ingestion. They inhibit the degradation of catecholamines norepinephrine, dopamine, and serotonin, resulting in symptoms that reflect excessive excitable neurotransmitters such as hypertension, tachycardia, tremors, seizures and hyperthermia (150).

MAOI toxicity is the result of three main events (150):

  • Intentional poisoning: Uncommon but happens nonetheless. Symptoms appear late, up to 32 hours after ingestion.

  • Drug-food interaction: This is the famous “tyramine reaction” which results in fatal hypertensive emergencies. It has a rapid onset, usually within 15-90 minutes after ingestion (see Table 4).

  • Drug-drug interaction: It occurs when coadministered with serotonin reuptake inhibitors and several analgesics. Essentially, any drug that releases catecholamines can trigger hypertensive crisis in individuals also using MAOIs (see table below).

Drug-food interactions

Drug-drug interactions



Smoked meat



Fluoxetine and other SSRIs





Red wine


Table 19: Significant interactions with MAOIs

Depressants are favorite drugs of choice to overdose on, particularly, barbiturates. However, newer classes such as benzodiazepines, which also happen to be the most commonly prescribed depressant in the US, are now the first line drugs for anxiety. These drugs have better safety profiles owing to their relatively high therapeutic index, but when taken concurrently with alcohol can lead to severe CNS depression. Symptoms of depressant overdose include sluggishness, drowsiness, reduced mental faculties, and in severe cases, respiratory depression and coma.

Reports in the recent years pointed to the possible increased likelihood of propylene glycol toxicity in neurocritical patients treated with high dose barbiturates. Propylene glycol is a pharmaceutical vehicle in the IV formulations of phenobarbital and pentobarbital. Its accumulation in the body to toxic levels may trigger the very seizures that the barbiturates intended to treat (151).

Barbiturates, in certain countries where euthanasia is legal, are used in combination with muscle relaxants for physician-assisted suicide (PAS).

Depressants should not be taken when operating machineries or driving (152).

Lithium poisoning is another concern with psychopharmacologic treatment. Due to its therapeutic dose (300-2700 mg/day) often overlapping with its toxic dose, the drug is known to cause frequent toxicity among its users, especially those with renal insufficiency and on diuretics. Lithium clearance is predominantly based on the glomerular filtration rate (GFR). Diuretics increase the reabsorption of lithium at the proximal tubule, the site where carbonic anhydrase inhibitors (e.g. acetazolamide) exhibit their effect (153).

Patient consent

The patient’s mental capacity is largely influenced by the severity of diagnosed disorder and plays a crucial role in determining the patient’s ability to give an autonomous and informed consent for psychiatric therapy, including the initiation of psychopharmacologic medications. Essentially, informed consent is both a legal and medical standard that is made up of three important components (154):

1) Ability to process information logically

2) Capacity to make decisions based on a set of given information

3) Voluntary action in the absence of coercive factors

Decisional capacity in psychiatric patients has been studied extensively in the last decade using the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). These studies found that decisional incapacity is common only in 20–30% of chronic psychiatric patients with acute and cognitive disorders, although this differs from state to state. Additionally, it has also identified several strong predictors (see table below) (154).



Positive symptoms



Negative symptoms

Social withdrawal


Severity of symptoms

The more severe the depression, the greater the likelihood of incapacity

Involuntary admission

Treatment refusal

Table 20: Predictors for decisional incapacity

Incapacity was noted mostly in patients with organic mental disorders such as dementia, psychosis and delirium. The remainder majority is actually capable of making treatment decisions. These include patients with personality and adjustment disorders.

Despite these predictors, the decision-making capacity of patients is not dependent on diagnostic categories of mental disorders; rather, it is the functional abilities such as understanding and practical reasoning that are the crucial elements in the assessment of decisional capacity.

Informed consent, based on appreciation, understanding and reasoning of the treatment proposed, varies across different diagnostic categories (155):


Studies show that schizophrenic patients’ appreciation, understanding and reasoning adversely affect MacCAT-T scores. In particular, they show, if at all, limited insight into their illness.

Mood disorders

Mania is a significant risk factor for incapacity, while mild to moderate depression has little effect on the decisional capacity of patients.

Mental retardation

Adults with mild mental retardation experience significant loss of appreciation and reasoning abilities, deeming them most of the time incapable of making informed decisions regarding their treatment.

Substance abuse disorder

Patients with this disorder are judged to have the full mental capacity to make autonomous treatment decisions, unless they also suffer from dementia or other issues due to substance abuse.

Anorexia nervosa

Since patients with this disorder experience distorted body image or denial of the consequences of abnormally low body weight, they generally show a loss of appreciation to the treatment proposed.

Primarily the clinician, prior to the start of treatment, psychopharmacological or otherwise, obtains informed consent. Obtaining informed consent follows a two-step process (55):

    1. Ensure that the patient has been given all information relevant to the treatment proposed – the risk, benefits, and prognosis both with and without treatment, alternative treatments and their risk and benefits.

    1. Ensure a voluntary choice free from coercion

Legal considerations

The clinician must be aware of the state laws governing the involuntary treatment of psychiatric patients, especially its limitations. As discussed in the previous sections, public safety is a powerful persuasion in eliciting legal action when compared to the wellbeing or even preservation of individual rights of the mentally ill individuals.

For example, in Rhode Island, the state can impose involuntary treatment of the mentally ill based on two legal premises (156):

1) Parens patriae, meaning “parent of the country,” gives the state sovereign authority to intervene and act on behalf of the mentally ill when they become mentally or physically incapable of caring for themselves.

2) Police power gives the state the authority to intervene on behalf of the public when its safety is threatened. Interventional actions include isolation and confinement of dangerous individuals. It applies to criminals, persons with contagious diseases and the mentally ill.

The question now becomes, can states make involuntarily hospitalized patients take their psychotropic medications?

Yes and no. Yes, because, majority of the US states respect personal decisions of patients, whether to initiate a treatment or forego it. This is true, even for many mentally ill individuals. No, because when found legally incompetent by law the refusal of medications may be overridden by a court order. Many states appoint legal guardians to consent for these patients.

A few states recognize the right of voluntary patients to refuse psychotropic medications. The reasons for refusal may be due to any of the following reasons (156):

    1. Delusional thinking (less likely)

    1. Previous intolerable side effect to the medication in question (more likely)

The second reason underscores the need for clinicians to explain the recommended psychopharmacologic treatments, including the benefits, adverse effects, and risks to their patients. The clinicians also need to explore fully the reasons behind the patient’s refusal. They may also opt to switch the patient to an alternate medication of the same class or another medication with more favorable side effects (156).

A second and third question follows the first one: Can involuntarily hospitalized patients be given emergency medications? How do these differ from involuntary medications?

Emergency medications are ordered when imminent danger to self or others is present. An example includes the use of short acting benzodiazepines and neuroleptics in restrained, dehydrated and delirious manic patient who continues to physically resist and bang his or her head against the bed frame. These emergency medications must be ordered acutely and their clinical need reassessed frequently (every few hours). They are only used when needed and no longer than a few days at the most (156).

Involuntary medications are those that need to be regularly taken by patients as per court’s order. As such, they are time-limited and their extension requires a clinical reevaluation of the patient, overall response to therapy and present endangerment to public safety.

The criteria for involuntary medications vary across states, but commonly include the following (156):

1) Incompetence to participate in decisions about treatment

2) Poor prognosis leading to dangerous behavior to self or others without the medications

3) History of noncompliance

Once these criteria are met, the clinician can then apply for the administration of involuntary medications with an accompanying affidavit supporting them.

Another ethical issue that emerged during the 1980s is the covert administration of psychotropic drugs during emergencies. Today, 25 states have included psychiatric advance directives (PADs) in the state legislatures to protect the autonomy of mentally ill patients during their periods of mental incapacity. PADs enable these patients to uphold their right to exercise choice and control over their own treatment during episodes when they are mentally incapable of making the decision.


Most psychoactive medications are either illicit or controlled drugs because of their propensity to cause dependence among its users. Drug dependence is implicated in four medical events:

1) Withdrawal and physical dependence

Physical dependence is characterized by the normal physiological adaptation of the body to the presence of a chronically administered drug. A drug dependent person needs to keep using the drug in order to prevent a withdrawal syndrome. Withdrawal syndrome results from abrupt discontinuation or dosage reduction, which has consequences ranging from mild to severely unpleasant and life-threatening complications.

2) Tolerance

A physiological state marked by a substantial decrease in drug sensitivity due to its chronic administration.

3) Psychological dependence

Psychological dependence refers to the intense and compulsive craving for the chronically administered drug. It is created when the “high” fades and the user administers another dose for an additional “fix”. While physical dependence will go away in days or weeks after drug use, psychological dependence can continue for years. This is the hallmark of “addiction”.

4) Overdose

Overdose is the administration of an excessively large and lethal dose of a drug (more than the therapeutic dose), leading to possible life-threatening complications.

Statistics on teen abuse

The 2008 Monitoring The Future (MTF) survey indicates use of illicit (street) drugs among teens has decreased in the US. However, more teens misuse prescription and OTC medications than any other illicit substance, except marijuana. A survey of 8th, 10th and 12th graders in public and private schools found in 2011 found that 2.1% of these teens reported that they had abused Ritalin and 4.1% reported that they had abused Adderall in the past year. In fact, the psychotropic medications, Adderall, Xanax and Valium are among the top 5 prescription drugs abused by teens, behind only the opioids, OxyContin and Vicodin (157). According to the CDC, there was a 91% increase in drug poisoning deaths among teens between the ages of 15-19 from 2000 to 2009 due to prescription drug overdose.

Commonly abused psychoactive drugs

Symptoms of overdose

Stimulants (amphetamine, phentermine, benzphetamine, methylphenidate)

Agitation, increased body temperature, seizures, hallucinations, death

Depressants / sleeping pills (barbiturates, benzodiazepines)

Respiratory arrest, clammy skin, dilated pupils, rapid pulse rate, coma, death

OTC dextromethorphan from cough syrup

Paralysis, loss of memory

Narcotics (codeine, methadone)

Respiratory depression, pinpoint pupils

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