Management of Medication-Induced Psychiatric Disorders.

INTRODUCTION

Consultation–liaison psychiatry, by definition, is the interface between psychiatry and other medical specialties and includes the facilitation of medical treatment of patients in general hospital settings.[1] It is not uncommon to find patients, who are on medication for physical disorders, presenting with psychiatric symptoms. However, it is very difficult to find out whether the presenting psychiatric manifestations have occurred due to underlying disease or as adverse effects of the medication given primarily for the physical illness. Hence, a psychiatrist and a physician should have adequate knowledge of the psychiatric side effects (PSEs) of various psychotropic and nonpsychotropic medications. The inadvertent PSEs of medication used for therapeutic purposes could cause problems to the patient care in various ways, such as affecting the drug compliance, affecting the patient–physician relation, and causing various psychiatric problems, which might be harmful to the patient and their caretakers.

Hence, a holistic approach to evaluate such patients is of paramount importance. Inaccurate diagnosis of the condition might have harmful long-term as well as short-term implications for the patient. It is difficult to confirm whether the presenting neuropsychiatric manifestations have occurred de novo or secondary to the medication used for medical illness or as a comorbidity of the psychiatric symptoms common with a psychiatric disorder. Establishing that the drug used for therapeutic purposes is the causative agent for the symptoms is critical because usually the effects caused by a drug are reversible and might disappear on discontinuing the drug.

Almost all kinds of drugs cause PSEs. According to a review study by Smith,[2] majority of drugs used for physical illnesses cause potential PSEs. Since a long time, drugs have been shown to have neuropsychiatric side effects. In the 1960s, reserpine, a drug used for hypertension, has been shown to cause depression as a result of likely monoamine depletion. The literature concerning the side effects of nonpsychotropic medication does help in gaining knowledge about these drugs and how to manage the adverse effects. This article outlines the assessment and management of various PSEs of the drugs used for therapeutic purposes. However, discussing the psychiatric complications of all the drugs used for various medical conditions is beyond the scope of this article.

ASSESSMENT AND EVALUATION

There are certain risk factors that predispose the patient to develop PSEs after using medication. These could be attributed to the chemical and pharmacological properties of the medication, the type of treatment, or certain patient characteristics. Alomar,[3] in their study, described some of these factors that include high dosage of drugs, parenteral administration, narrow therapeutic index, polypharmacy, patients at extremes of age, patients with a prior mental illness, and patients who are critically ill. These factors are described in Table 1.

Table 1

Factors predisposing a patient to psychiatric side effects

Factors predisposing	Example
Drug related	Pharmacokinetics
	Pharmacodynamics
	Dosage
	Therapeutic index
Treatment related	Route of administration
	Polypharmacy
	Duration of treatment
Patient related	Age, gender
	Comorbidities
	Genetic predisposition

MECHANISM

The mechanism by which a drug causes a side effect is dependent on its pharmacokinetics and pharmacodynamics.

Pharmacodynamic mechanisms

Both nonpsychotropic and psychotropic drugs influence the neurotransmitter systems directly or indirectly leading to an imbalance causing the PSEs.

PHARMACOKINETIC MECHANISMS

Pharmacokinetic mechanisms are relevant when PSEs follow a dose–response curve

Various mechanisms such as polymorphisms of the hepatic enzymes, disease states, and drug-to-drug interactions that cause metabolic inhibition lead to low clearance of the drug which in turn increases the serum concentrations of the drug, leading to psychiatric manifestations.

Adverse drug reactions (ADRs) are of two types:

First is the Type A or augmented reactions in which the medicine’s pharmacological activity that might be unrelated to the intended therapeutic effects causes the adverse effects. These are dose related. Majority of the ADRs are of this type

Second is the Type B or bizarre reactions that are unpredictable, idiosyncratic, and are not dose related. These include the allergic and the hypersensitivity reactions mediated by the immunological factors. The characterisics of the types of drug reactions are mentioned in Table 2.

Table 2

Types of adverse drug reactions

Type A	Type B
Dose dependent	Not dose dependent
Predictable	Unpredictable
High morbidity with low mortality	Low morbidity with high mortality
Dose reduction helps in managing the reaction	Drug withdrawal helps in managing the reaction

ESTABLISHING AN ASSOCIATION

Diagnosing a drug-related PSE could be complicated by many factors such as preexisting mental illness, physical illness, nonprescribed agents, and coprescribed medication. Criteria determining the causality of drug in the development of PSEs include:

A temporal relationship between the drug exposure and the PSE

Plausible pharmacological mechanism which explains the occurrence of the PSE

Definitive evidence of the specific psychiatric adverse effects occurring with the suspected drug

Response of symptoms to the withdrawal of the drug

A positive effect of re-challenge with the same drug.

Diagnosing medication-induced psychiatric disorders is often post hoc, and, in view of their similar presentation with the primary psychiatric illness, can be challenging. Hence, any psychiatric symptom could be considered as a potential PSE until its relation to the previous administration of drugs is proved beyond any doubt.

Challenge, de-challenge, and re-challenge help in establishing the causality of the drug. De-challenge refers to the stopping of the drug, usually after an adverse drug effect or at the end of a planned treatment. A positive de-challenge results in the disappearance of the ADR after stopping the drug, whereas a positive re-challenge results in the ADR reappearing after restarting the drug.

The ADR probability scale developed by Naranjo et al.[4] (also known as Naranjo scale, Naranjo algorithm, or Naranjo nomogram) is a 10-item scale with good reliability and validity for predicting the probability of adverse reactions to drugs. This is shown in Table 3.

Table 3

The Adverse Drug Reactions Probability Scale

Questions	Yes	No	Unknown/NA
Are there previous conclusive reports on this reaction?	+1	0	0
Did the ADR appear after the suspected drug was administered?	+2	−1	0
Did the ADR improve when the drug was discontinued?	+1	0	0
Did the ADR appear with re-challenge?	+2	−1	0
Are there alternative causes for the ADR?	−1	+2	0
Did the reaction appear when placebo was given?	−1	+1	0
Was the drug detected in the blood at toxic levels?	+1	0	0
Was the ADR more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0
Was the ADR confirmed by any objective evidence?	+1	0	0

ADR – Adverse drug reaction; NA – Not available

The scores are then assessed as ≥9 = definite; 5–8 = probable; 1–4 = possible; ≤0 = doubtful. This scale helps in the clinical diagnosis of PSEs.

The World Health Organization Collaborating Centre for International Drug Monitoring-the Uppsala Monitoring Centre has also put forth an assessing system to determine the causal relation between a drug and a suspected adverse effect. This is shown in Table 4.

Table 4

World Health Organization Collaborating Centre for International Drug Monitoring - the Uppsala Monitoring Centre causality categories

Causality term	Assessment criteria
Certain	Event or laboratory test abnormality, with plausible time relationship to drug intake
	Cannot be explained by disease or other drugs
	Response to withdrawal plausible
	Event definitive pharmacologically or phenomenologically
	Re-challenge satisfactory, if necessary
Probable/likely	Event or laboratory test abnormality, with reasonable time relationship to drug intake
	Unlikely to be attributed to disease or other drugs
	Response to withdrawal clinically reasonable
	Re-challenge not required
Possible	Event or laboratory test abnormality, with reasonable time relationship to drug intake
	Could also be explained by disease or other drugs
	Information on drug withdrawal may be lacking or unclear
Unlikely	Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable
	Disease or other drugs provide plausible explanations
Conditional/unclassified	Event or laboratory test abnormality
	More data for proper assessment needed, or
	Additional data under examination
Unassessable/unclassifiable	Report suggesting an adverse reaction
	Cannot be judged because information is insufficient or contradictory
	Data cannot be supplemented or verified

PSYCHOTROPIC DRUG INTERACTIONS

Using antipsychotics in conjunction with other drugs may result in pharmacokinetic interactions that produce various adverse reactions. Owing to properties such as large volume of distribution, lipophilicity, and extensive protein binding, antipsychotics have poor metabolic clearance.

First-generation antipsychotics such as phenothiazines are metabolized primarily by CYP2D6 and to some extent by CYP1A2 and CYP3A4. Second-generation antipsychotics such as phenothiazines undergo biotransformation primarily by CYP450s. Clinically significant interactions have been reported in patients taking fluoroquinolones or fluvoxamine which are potent inhibitors of CYP1A2.

Tricyclic antidepressants (TCAs) are metabolized by CYP1A2, 2C9/19, 2D6, and 3A4. Using TCAs with other enzyme inhibitors causes clinically significant drug interactions. Majority of second-generation antidepressants undergo extensive hepatic oxidative metabolism by CYP450 isoenzymes. However, newer antidepressants such as mirtazapine and reboxetine have not been reported to result in clinically significant drug interactions.

Majority of benzodiazepines are metabolized by CYP3A4, followed by CYP2C19. Common drug interactions involving benzodiazepines often occur due to elevated serum concentrations, thereby resulting in an increase in the pharmacologic effects of the drug.

Clinically relevant drug interactions involving mood stabilizers are due to induction or inhibition of drug metabolism mediated by the CYP450 system. Lithium is similar to sodium, because of which drugs such as osmotic diuretics that inhibit the sodium reabsorption at the proximal convoluted tubule reduce lithium concentrations. Other drugs such as theophylline and verapamil have also been shown to decrease lithium levels.[5]

DRUGS CAUSING PSYCHIATRIC SIDE EFFECTS

As described earlier, majority of prescribed drugs acting on various systems of the body can cause PSEs. Before describing each drug class in detail, a summary of the drugs causing PSEs is given in Table 5.

Table 5

Overview of drugs causing psychiatric side effects

Class of drugs	Examples
Cardiovascular medications	Beta blockers, ACE inhibitors, alpha agonists, digoxin, statins
Dermatological medications	Cyclosporine A, methotrexate, infliximab, etanercept, ustekinumab, vemurafenib, and ipilimumab
CNS medications	Anticonvulsants, anti-Parkinsonian drugs
Antimicrobials	Antibiotics, antitubercular drugs, antivirals, antifungal drugs
Anticancer agents	Ifosfamide, 5-fluorouracil, asparaginase, vincristine
Immunomodulators	IFNs, interleukins, isotretinoin
Hormones	GnRH agonists, progestins
Steroids	Corticosteroids, anabolic androgenic steroids
Anesthetic agents	Ketamine, propofol, suxamethonium
Oral hypoglycemic agents	Metformin, glimepiride
Muscle relaxants	Baclofen, dantrolene
Respiratory system drugs	Antihistamines, decongestants
Reflux medications	Proton pump inhibitors, H2 receptor antagonists
Analgesics	Aspirin, ibuprofen, indomethacin

ACE – Angiotensin-converting enzyme; GnRH – Gonadotropin-releasing hormone; CNS – Central nervous system; IFN – Interferon

Various psychiatric symptoms can be caused by the above-mentioned drugs. Table 6 outlines the various psychiatric symptoms and the drugs implicated.

Table 6

Psychiatric side effects and drugs implicated

Symptom	Drugs implicated
Anxiety	Steroids, antivirals, clonidine, nitrates, penicillin
Depression	Steroids, β blockers, clonidine, antiretrovirals, GnRH agonists, H2 blockers, IFNs
Delirium	ACE inhibitors, steroids, antibiotics, anticholinergics, β blockers, H2 blockers
Insomnia	Steroids, clonidine, salbutamol, proton pump inhibitors, skeletal muscle relaxants, quinolones
Psychosis/hallucination/delusion	Steroids, clonidine, proton pump inhibitors, quinolones, Salbutamol, H2 blockers
Manic reaction	Dopamine agonists, antidepressants, steroids, sympathomimetics, H2 blockers, thyroxin, chloroquine, baclofen
Sexual side effects	Diuretics, anticonvulsants, antihistamines, muscle relaxants
Seizures	Antimalarials, fluoroquinolones, systemic steroids, CNS stimulants, cyclosporine, tricyclics
Suicidal ideation	Nitrates, antiretrovirals, antifungals, cycloserine, fluoroquinolones, IFN
Substance addiction	Cough syrups, steroids, ketamine, loperamide, dextromethorphan
Cognitive dysfunction	H2 blockers, corticosteroids, NSAIDs, anticonvulsants, antidepressants, anticholinergics

ACE – Angiotensin-converting enzyme; GnRH – Gonadotropin-releasing hormone; NSAID – Nonsteroidal anti-inflammatory drugs; IFN – Interferon; CNS – Central nervous system

Cardiovascular drugs

Drugs acting on the cardiovascular system cause neuropsychiatric effects either directly (β-blockers) by crossing the blood–brain barrier and affecting the brain or indirectly (diuretics) by causing metabolic or electrolyte disturbances, leading to psychiatric symptoms.[6]

One important confounding factor to be considered while assessing a patient on cardiovascular drugs is the heart disease itself, as most of the patients with a cardiovascular disease have psychiatric symptoms. For example, depression and anxiety are common in post-myocardial infarction patients, post-coronary artery bypass graft patients, and patients with coronary artery disease.[789] Further, some of the critically ill patients in cardiac intensive care units have symptoms such as mood liability, disorientation, and hallucinations that characterize delirium. Hence, it is important to take proper clinical history while assessing a patient. The various cardiovascular drugs and their side effects are shown in Table 7.

Table 7

Cardiovascular drugs and their psychiatric side effects

Class of cardiovascular drug	Side effects
β-blockers	Sedation, sleep impairment, psychosis, depression, dysphoria and delirium
ACE inhibitors	Altered mood, anxiety, fatigue, parasomnias, sedation, and delirium
Alpha adrenergic agonists	Lethargy, depression, agitation, anxiety, confusion, delirium and psychosis
Digoxin	Delirium, fatigue, depression, and psychosis
Diuretics	Fatigue, lethargy, malaise, anorexia, mania, depression, and rarely delirium
Calcium channel blockers	Fatigue, sedation, confusion, and delirium
Statins	Depression, fatigue, anxiety, and occasional sleep disturbances
Nitrates	Hallucinations, acute confusional state, delirium, and rarely suicidal ideation
Vasodilators	Fatigue, depression, mild anxiety, psychosis, and delirium

ACE – Angiotensin-converting enzyme

Dermatological medications

Various drugs used for treating dermatological conditions, such as psoriasis, acne, or dermatoses, cause neuropsychiatric side effects that range from mild headaches to encephalopathies.[10] Various dermatological medications and their psychiatric side effects are described in Table 8.

Table 8

Dermatological drugs and their psychiatric side effects

Drug	Side effects
Cyclosporine	Headaches, tremors, paresthesia, overt psychosis, mania, and seizures
Methotrexate	Psychosis and mania
Ipilimumab	Headaches, dizziness, lethargy, weakness, and transient sensory and motor peripheral neuropathies, MERS
IFN – 2αb	Depression, suicidal ideation
Tetracyclines, isotretinoin, acetretin	Headache, fatigue

IFN – Interferon; MERS – Middle East respiratory syndrome

Antimicrobial agents

Antibiotic drugs are used very commonly across the world, and almost all groups of antibiotics are associated with adverse neuropsychiatric effects. These can directly affect the functioning of the neuronal cells by crossing the blood–brain barrier or acting on the microbiome in the gut and cause dysbiosis.[11] Various antibiotics and their psychiatric side effects are described in Table 9.

Table 9

Antibiotics and psychiatric side effects[11]

Antibiotic class	Neuropsychiatric adverse effects
β-lactams	Epilepsy
Macrolides	Tinnitus, anxiety, dizziness, vertigo, mania, disorientation, psychosis, hallucinations, delirium, and major depression
Fluoroquinolones	Headache, dizziness, somnolence and insomnia, psychosis, delirium, seizures, peripheral neuropathy, and suicidal ideation/behavior
Aminoglycosides	Peripheral neuropathy, delirium, encephalopathy, and neuromuscular impulse inhibition
Polymyxins	Headache, dizziness, paresthesia, ataxia, convulsions, and apnea
Glycylcycline	Headache, dizziness, and insomnia
Sulfonamides	Headache, drowsiness, tremor, aseptic meningitis, delirium, and psychosis
Nitrofurantoin	Headache, peripheral neuropathy, dizziness, and drowsiness
Lipoglycopeptides	Aggressiveness, agitation, restlessness, visual and auditory hallucinations, psychosis, and delirium

ANTIFUNGALS

Many antifungal treatments may cause neuropsychiatric side effects such as confusion, agitation, myoclonus, hallucinations, and delirium. Some of these drugs cause the side effects by directly crossing the blood–brain barrier, while some (itraconazole) cause the side effects indirectly by affecting the neurotransmitter levels.

Amphotericin has been associated with various adverse effects such as headache, neuropathy, convulsions, tremor, paresis, mood disorders, suicidal ideation, and altered sensorium.

Antiparasitics

Antiparasitic drugs cause few neuropsychiatric adverse effects, and most of these are related to the dead parasite rather than the drug itself. Some of the adverse effects include headache, dizziness, fatigue, convulsions, visual hallucinations, and rarely delirium. The drugs include albendazole, praziquantel, ivermectin, pyrantel, and nitazoxanide.

Antimalarial drugs

Mefloquine is the most common antimalarial drug that is associated with PSEs. These include depression, anxiety, paranoia, confusion, memory difficulties, impaired attention, and hallucinations. Headache, tinnitus, lightheadedness, and dizziness are also observed. In some patients receiving mefloquine, a condition characterized by convulsions, tremor, and confusion called the “Postmalaria Syndrome” is seen. Quinine and chloroquine cause few neuropsychiatric adverse events.

Artemisinin derivative artesunate is associated with adverse effects such as headache, dizziness and tinnitus, peripheral neuropathy, or isolated paresthesia. Other artemisinin derivative artemether has been found to cause ataxia, clonus, or sensory disturbance.

Antivirals

Antivirals such as acyclovir and ganciclovir can cause psychological symptoms such as hallucinations, anxiety, lethargy, and frank delirium when given in high doses. Depression, anxiety, hallucinations, and aggressive irritability have been reported with Foscarnet. Anti-HIV agents such as didanosine are associated with several psychiatric adverse effects such as lethargy, depression, anxiety, emotional liability, delirium, insomnia, and psychosis. Severe suicidal ideation has been described with nonnucleoside reverse transcriptase inhibitor such as efavirenz.[12]

Disturbance in the gut microbiota due to antibiotics causes PSEs such as schizophrenia, mood disorders, autism, irritable bowel syndrome, cognitive decline, and anxiety disorders, especially with long-term usage of the drugs.

Antituberculosis drugs

With tuberculosis (TB) still being a major health problem, anti-TB agents are quite commonly used. Most of the regimens include polypharmacy which increases the chances of adverse effects. Some of the anti-TB agents are associated with neuropsychiatric side effects.

Isoniazid is a first-line anti-TB drug that interferes with pyridoxine-dependent coenzymes and can cause Vitamin B6 deficiency. This can affect the nervous system. It affects the peripheral nervous system and central nervous system (CNS). These side effects include headaches, optic neuropathy, muscle twitching, restlessness, insomnia, psychiatric symptoms, peripheral neuropathy, seizures, and, rarely, cognitive decline.[13]

Rifampicin, another first-line anti-TB drug, causes CNS adverse effects by inducing both the hepatic and intestinal cytochrome P450 enzyme systems as well as the P-glycoprotein transport system.[14] These include seizures, headache and drowsiness, ataxia, and dizziness.

Other anti-TB agents are also associated with CNS side effects. These are described in Table 10.[15]

Table 10

Neuropsychiatric side effects with antituberculosis agents

Drug	Adverse effect
Common (>10%)
Cycloserine	Psychosis
Isoniazid	Headaches, seizures with overdosage
Linezolid	Headaches
Meropenem	Headaches
Ethionamide	Peripheral neuropathy
Aminoglycosides (amikacin, kanamycin most often)	Hearing loss
Thioacetazone	Tinnitus, giddiness
Occasional (1%-10%)
Cycloserine	Anxiety, seizures, headaches
Ethionamide	Dizziness, headaches
Linezolid	Insomnia, serotonin syndrome
Quinolones	Headaches, insomnia, dizziness, somnolence
Isoniazid	Peripheral neuropathy
Ethambutol	Retrobulbar optic neuropathy
Aminoglycosides	Vestibular dysfunction
Rare (<1%)
Cycloserine	Dizziness, tremor, insomnia, suicide, slurred speech agitation, bipolar exacerbations, suicide
Ethambutol	Headaches, confusion, peripheral neuropathy and dizziness
Ethionamide	Behavioral problems
Isoniazid	Ataxia, dizziness, agitation, insomnia, altered mental status, and psychosis
Meropenem (with clavulanate)	Agitation, confusion, delirium, seizures, somnolence
Quinolones	Tourette - like syndrome, altered mental status, agitation, myoclonus, seizures and muscle jerks, psychosis
Rifampicin	Ataxia, headaches and dizziness

Anticancer drugs

Anticancer agents commonly cause neuropsychiatric side effects. Ifosfamide is known to cause frightening, vivid visual hallucinations at toxic doses.[16] Occasionally, psychosis characterized by terrifying hallucinations, delusions of persecution and fear along with depressive mood, anxiety, insomnia, and disorganized speech can develop. Hypoactivity and negative symptoms can alternate with hypomaniacal behavior.

Procarbazine, an alkylating agent, has been known to cause manic psychosis.[17] Immunomodulatory drugs are often associated with psychiatric manifestations of CNS toxicity. Interferon a-2b, b, and c are associated with psychosis, depression, and suicidal ideations. Patients with preexisting psychiatric illness are particularly prone to develop these side effects. Interleukin-2 is associated with neuropsychiatric symptoms such as hallucinations. Other drugs such as interleukin-1 and rituximab are associated with recurrent psychotic episodes.[18]

Anti-Parkinsonian drugs

Neuropsychiatric adverse effects are common with drugs used for Parkinson’s disease (PD) such as levodopa, dopamine receptor agonists, selegiline, amantadine, and anticholinergic agents. These drugs cause severe disability to the patient and need to be carefully monitored. These are described in Table 11.

Table 11

Neuropsychiatric side effects with anti-Parkinsonian drugs[12]

Drug	PSE
L-DOPA	Insomnia, cognitive impairment, psychosis, depression, hypomania, visual hallucinations, agitation, altered mental status
Dopamine agonists	Psychomotor agitation, akathisia, insomnia, sedation, hallucinations, psychosis, cognitive impairment, and delirium
Amantadine	Visual hallucinations, mood changes, fatigue, euphoria, decreased concentration, sleep disturbances, psychosis, delirium
Selegiline	Agitation, insomnia, psychosis
COMT inhibitors	Hallucinations, insomnia, delirium
Benztropine	Sedation, psychosis, delirium, abuse potential
Biperiden	Sedation, psychosis, delirium
Procyclidine	Anxiety, psychomotor agitation, delirium
Benzhexol	Sedation, psychosis, delirium, abuse potential

L-DOPA – Levodopa; COMT – Catechol-o-methyl-transferase; PSE – Psychiatric side effects

According to a study done by Cummings,[19] 30% of patients using Parkinsonian drugs develop visual hallucinations, 10% exhibit delusions, and 15% have periods of confusion. In addition, 10% experience anxiety, 10% have euphoria, and 1% have mania. Anxiety and sleep disturbances have also been reported with the use of these anti-Parkinsonian drugs.

Increasing age and dementia are the most common risk factors for neuropsychiatric adverse effects in patients with PD taking anti-Parkinsonian drugs. The risk is also found to be high in patients receiving higher dosages of levodopa, adjunctive therapies such as amantadine and anticholinergics, or dopaminergic agonists.

Friedman[20] observed that the psychoses caused due to levodopa may be associated with a clear sensorium or occur against a background of confusion. The signs of impending psychoses include worsening sleep disturbance, including vivid dreams and nightmares. This slowly progresses to visual hallucinations and paranoid/grandiose delusions. Mania, anxiety, and hypersexual behavior can also be seen. All of these symptoms occur in other psychiatric disorders and in PD itself and cannot always be attributed to drugs. The neurochemical basis of drug-induced psychosis in patients with PD include stimulation of the dopaminergic receptors in the mesolimbic region and dysfunction of serotonergic.

Patients with the above-mentioned risk factors are likely to develop delirium due to dopamine excess and acetylcholine deficiency, both in absolute amounts and/or relative to each other resulting in confusion, restlessness, and floccillation. Varius dermatological medications and their psychiatric side effects are described in Table 8.

Anticonvulsant drugs

Psychiatric and behavioral side effects are very common in patients using antiepileptic drugs. These adverse effects often cause several problems, both to the patient and to the treating physician, leading to poor adherence to the medication, suboptimal dosage, and discontinuation of the treatment regimen. Around one-fifth of adult patients with epilepsy on antiepileptics develop psychiatric and behavioral side effects. These include mood disorders, insomnia, psychosis, and aggression. Table 12 describes the PSEs associated with individual antiepileptic drugs:

Table 12

Neuropsychiatric side effects with anticonvulsant drugs[12]

Antiepileptic drug	PSE
Benzodiazepines	Cognitive impairment, delirium, agitation, sedation, psychosis, hallucinations, and withdrawal syndrome
Phenobarbital	Cognitive impairment, sedation, insomnia, psychosis, depression, paradoxical agitation, and delirium
Phenytoin	Agitation, insomnia, delirium
Sodium valproate	Sedation, hallucinations, depression, delirium
Ethosuximide	Irritability, insomnia, psychosis, mood changes, delirium
Carbamazepine	Depression, psychosis, agitation, sedation, cognitive impairment, delirium
Vigabatrin	Lethargy, irritability, agitation, major depression, agitation, psychosis, cognitive impairment
Topiramate	Depression, emotional liability, psychosis, cognitive impairment
Tiagabine	Psychosis, depressive symptoms, sedation
Gabapentin	Agitation, sedation, fatigue
Levetiracetam	Irritability, sedation and psychosis
Brivaracetam	Not significant
Lamotrigine	Agitation, depression, sedation, psychosis

PSE – Psychiatric side effects

Hormones

Progestins and estrogens, used commonly in gynecological practice, are the major hormones associated with PSEs. Progestins are associated with varied side effects such as anxiety, irritability, and depression. Estrogens are usually associated with positive effects on mood, and studies have been done to investigate the antidepressant effects of estrogen.[12] However, these studies have provided inconsistent results.

Gonadotropin-releasing hormone agonists are known to cause depressive symptoms.[21] Patients taking levothyroxine could develop anxiety, tremulousness, and hyperactivity secondary to the development of levothyroxine-induced hyperthyroidism. Various hormones and their psychiatric side effects are described in Table 13.

Table 13

Neuropsychiatric side effects with hormones

Hormone	Side effect
Progestins	Anxiety, irritability, depression
Estrogens	Euphoria, manic reaction
GnRH agonists	Depression
Levothyroxine	Anxiety, tremulousness, hyperactivity

GnRH – Gonadotropin-releasing hormone

Immunomodulators associated with various PSEs, particularly depression. In most of the cases, the psychiatric complications occur within the first 3 months of starting the therapy. Using an antidepressant such as SSRI helps stabilize the symptoms. Certain studies have postulated that hypometabolism in the prefrontal cortex may contribute to these neuropsychiatric side effects.[222324] These are described in Table 14.

Table 14

Psychiatric side-effects of immunomodulators[12]

Drug	Psychiatric side effect
NSAIDS	Insomnia, mood disorders, psychosis, fatigue, lethargy, agitation, anxiety, delirium
Corticosteroids	Lethargy, anxiety, agitation, mood disturbances, personality changes, psychological dependence, sleep disturbances, psychosis, delirium
Cyclosporine A	Cognitive impairment, depression, anxiety, psychosis, delirium
Tacrolimus	Depression, psychosis, anxiety, delirium
Sulfasalazine	Delirium, sleep disturbances
H1 receptor antagonists	Sedation, agitation, psychosis, delirium
H2 receptor antagonists	Insomnia, depression, suicidal ideation, cognitive impairment, agitation, lethargy anxiety, hallucinations, and delirium
Methotrexate	Personality changes, irritability, delirium

NSAIDS – Nonsteroidal anti-inflammatory drugs

Steroids

Corticosteroids are some of the most commonly prescribed medications for medical disorders. They are commonly associated with PSEs. These include insomnia, euphoria, depression, mood changes, delirium, lethargy, personality changes, anxiety, psychosis, and agitation. Usually, euphoria and hypomania develop with short-term use and depression with long-term use.[25]

Increasing use of anabolic androgenic steroids, especially in athletes and bodybuilders, leads to the development of PSEs such as homicidal rage, aggression, acute psychosis, mood liability, delirium, increase in libido, and anger.[26]

These side effects are usually dose dependent and resolve on discontinuing the medication. Occasionally, they might persist beyond 1 month despite medication.

Anesthetics

Ketamine, an NMDA receptor antagonist, used as an anesthetic is known to cause perceptual distortions, hallucinations, dissociation, referential ideas, and schizophrenia-like psychosis.[27] Propofol, another anesthetic drug used for induction, is associated with side effects such as dizziness, agitation, chills, somnolence, and delirium.

Decongestants

Decongestants are associated with an atropine-like psychosis that presents with altered mental status, hallucinations, agitation, and memory problems. These drugs are contraindicated in patients taking MAO inhibitors as they cause very high levels of norepinephrine, leading to hypertensive crisis. Ephedrine is found to be associated with restlessness, dysphoria, irritability, anxiety, and insomnia.[28]

Reflux medications

Both proton pump inhibitors and H2 receptor antagonists are sometimes associated with serious neuropsychiatric side effects such as altered mental status, agitation, depression, and psychosis. These occur rarely in the general population but are more common in the elderly and people with hepatorenal dysfunction.

H2 receptor antagonist cimetidine has significant drug interactions due to its nonselective cytochrome P450 inhibition. It increases the blood levels of TCAs, resulting in tachycardia and other adverse effects. It is also associated with anxiety, insomnia, and sexual dysfunction. Ranitidine and cimetidine are also associated with a withdrawal syndrome that includes insomnia, anxiety, and irritability.[2930]

Vitamins

Vitamins play an important role in mental health. Various mental health conditions could develop due to vitamin deficiencies. Folate deficiency has been linked to depression. Vitamin B1 deficiency is associated with symptoms such as amnesia, anxiety, irritability, depression, and insomnia. Vitamin B12 deficiency is associated with mood disorders, psychosis, irritability, confusion, and dementia. Vitamin D deficiency has been associated with acute mood disorders, psychosis, and depression.[31]

Other drugs

Ondansetron, a 5-HT3 antagonist used as an antiemetic, is strongly associated with anxiety.[32] Metformin, an oral hypoglycemic agent, is known to cause anxiety, depression, and confusion. Salbutamol and aminophylline cause insomnia, agitation, euphoria, and delirium.[12]

The list of drugs causing PSEs is long and the types of psychiatric conditions due to various drugs used for other therapeutic indications are many. Table 15 shows a summary of some important drugs and major psychiatric manifestations.

Table 15

Pharmacological treatment – Potential psychiatric side effects

	Psychotic symptoms	Depression	Mania	Anxiety
Amantadine	+	+	+	+
Aminoglycosides	+
Amphetamines	+	+	+	+
Anabolic steroids	+	+	+	+
Anesthetics			+
Anticholinergics	+	+		+
Antihistamines		+	+
Antitubercular agents	+	+		+
Antivirals	+	+		+
Baclofen	+	+	+	+
Barbiturates	+	+	+	+
Benzodiazepines	+		+	+
β-blockers	+	+	+	+
Bromocriptine	+		+	+
Cephalosporin	+		+
Chloroquine	+	+	+	+
Clonidine	+	+	+	+
Corticosteroids	+	+	+	+
Digoxin	+	+	+
Disulfiram	+	+	+	+
Interferon-α	+	+	+	+
Isotretinoin	+	+
L-DOPA	+	+	+	+
Lidocaine	+	+	+	+
Mefloquine	+	+	+	+
Methyldopa	+	+		+
Methylphenidate		+	+	+
Metoclopramide		+	+	+
Metronidazole	+
Opioids	+	+	+	+
Oral contraceptives		+		+
Procainamide	+	+	+	+
Pseudoephedrine	+			+
Quinidine	+			+
Quinolones	+	+		+
Thiazide diuretics		+

L-DOPA – Levodopa. + – The symbol indicates the occurrence of adverese effect with the drug class

ELECTROLYTE IMBALANCE

Many drugs used in various medical conditions are notorious in the development of disturbance in electrolyte concentrations which can result in psychiatric symptoms. The common conditions physicians come across include hyponatremia. Drugs causing hyponatremia such as diuretics, ACE inhibitors, anticonvulsants, and proton pump inhibitors cause PSEs that include seizures, psychosis, acute confusion, and coma.

METABOLIC SYNDROME

Drugs that predispose a person to develop metabolic syndrome increase cardiovascular morbidity and mortality. Factors such as lifestyle changes, use of psychotropic drugs, and genetic predisposition have resulted in an increase in incidence of the syndrome among psychiatric patients. Metabolic syndrome also causes psychiatric manifestations such as depression[33] and cognitive side effects and has become one of the greatest challenges in modern psychiatric practice.[34]

SEROTONIN SYNDROME

Though primarily caused by SSRIs, there are other drugs that can precipitate overactivation of 5HT2 receptors, resulting in syndrome consisting of nausea, vomiting, diarrhea, anxiety, agitation, lethargy, hypertension, altered sensorium, and coma. Rarely, if not recognized early, it can be life-threatening.

MANAGEMENT

Consultation–liaison psychiatrists commonly encounter drug-induced psychiatric symptoms in various clinical settings, especially the emergency services or critical care units. Thorough knowledge of these side effects is of high importance.[35] Psychiatrists should work in coalition with the treating physician for the appropriate management of these side effects. Various drug classes and their psychiatric side effects are summarized and described in Table 15.

Many conditions other than drug-induced PSEs need to be considered as differentials, and the patient should be thoroughly investigated to rule out all the other possibilities. Some of the differential diagnoses to be considered include are given in Table 16.[36]

Table 16

Medication associated psychiatric side effects - Differential diagnoses

Diagnosis	Possible
Diagnoses other than PSE	Exacerbation of an existing psychiatric illness
	Underlying medical illnesses with psychiatric symptoms
	Psychiatric decompensation in persons with no evident susceptibility
PSE - Differential diagnoses	Withdrawal-related PSE
	Intoxication-related PSE
	PSEs at usual doses

PSE – Psychiatric side effects

Risk factors associated with these side effects need to be assessed. The primary illness and any associated psychiatric complications should also be considered.

INVESTIGATING A PATIENT PRESENTING WITH DRUG-ASSOCIATED PSYCHIATRIC SIDE EFFECT

The following laboratory and metabolic assessments are useful for a comprehensive diagnostic evaluation of the patient.[37] These are mentioned in Table 17.

Table 17

Investigations

Type of investigation	Example
Blood investigations	CBP; blood glucose levels
Metabolic and drug screening	Liver and renal function tests; thyroid profile; assessment of Vitamin B12 and Vitamin D; drug levels including alcohol concentration; urine drug screening
Imaging	Chest X-Ray, head computerized tomography, magnetic resonance imaging
Screening tests	Tests related to syphilis, HIV, hepatitis B COVID
Miscellaneous	ECG; autoimmune screening

CBP – Complete blood picture; ECG – Electrocardiogram

TREATING A PATIENT WITH DRUG- ASSOCIATED PSYCHIATRIC SIDE EFFECT

After diagnosing a drug-associated PSE, the patient can be treated by pharmacological and nonpharmacological methods.

Pharmacological management

The pharmacotherapy of the primary medical illness needs to be optimized to the patient based on his age, renal and hepatic status, and comorbidities. In consultation with the treating physician, the offending drug could be stopped and switched to another drug with similar therapeutic benefits.

When to start a psychotropic?

In most of the cases, the psychiatric symptoms are reversible and remit with the cessation of the offending drug. However, appropriate psychotropics such as antipsychotics and mood stabilizers might be necessary depending on the severity and duration of the symptoms. It is better to start the psychotropics at a minimal effective dose and increase the dose gradually according to the patient’s condition. If the patient is unable to tolerate a particular psychotropic drug, a safer drug can be considered. The patient’s symptoms can be periodically assessed, and depending on the response, the drug can be slowly tapered off. If the patient has an underlying syndromic mental illness, it can be treated accordingly with the required psychotropic medication along with the medication for the physical illness

Nonpharmacological management

Nonpharmacological measures such as maintaining a familiar environment, re-orientation of the patient, regular visits by same personnel and family, psychoeducation of the patient, as well as the family members, also help in decreasing the PSEs. Close monitoring of the side effects of the psychotropic medication is necessary. The following algorithm delineates the assessment and management when a patient presents with a PSE. The general principles of managing a patient with medication induced psychiatric side effects are mentioned in Table 18.

Table 18

General principles of management

Identify the causes, and maintaining factors for PSE

Review medication history: Total number, type of drugs, use of over-the-counter drugs or drugs from alternative medicine, any recent change and their association with emergence of psychiatric symptoms

Manage the causes: Discontinue or reduce the dose of causative agent, remove unnecessary medications

Communication with primary treating team

Educate the family about the side effects

Monitor patient clinical status

Nonpharmacological measures

Pharmacological agents

PSE – Psychiatric side effects

Figure 1 depicts an outline of assessment, evaluation, and the management of a patient presenting with drug associated PSEs:

Figure 1

Management of Medication-induced psychiatric disorders

CONCLUSION

It is not uncommon to see patients presenting to a psychiatrist having comorbid medical illnesses, for which they are using medication. There are no specific laboratory investigations or tests to differentiate primary mental illness from a psychiatric symptom secondary to medication use and presents a diagnostic challenge for the treating physician and psychiatrist. Psychiatric manifestations can be due to primary mental illness or induced by medications used for other therapeutic purposes or could also be secondary to some other adverse effect of the drug (e.g., psychosis secondary to hyponatremia, secondary to diuretic use). Almost all the drugs used for therapeutic purposes have PSEs. Identifying a medication as the definitive cause of psychiatric symptoms is difficult but helps in specific treatment. Evaluating patients presenting with psychiatric symptoms due to drugs prescribed for medical conditions is important because more often than not, the symptoms are reversible, and there would be good recovery if the offending medication is discontinued. Constant liaison with the treating physician plays an important role in the management of the side effects. Management includes a holistic assessment and evaluation of the patient. The offending drug can be gradually tapered or stopped completely or switched to safer drug with similar therapeutic benefits. Nonpharmacological measures such as maintaining a homogenous environment, regular reorientation of the patient, and regular visits by the family also help in the management of the PSEs in a critical care setting.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.