European Review for Medical and Pharmacological Sciences 2013; 17(Suppl 1): 65-85 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases

A. TESTA, R. GIANNUZZI, F. SOLLAZZO*, L. PETRONGOLO**, L. BERNARDINI**, S. DAINI**

Department of Emergency Medicine, “A. Gemelli” Hospital, Catholic University of the Sacred Heart, Rome, Italy *Neuropsychiatric Pathology, Psychiatric Hospital “Parco dei Tigli”, Teolo (Padua), Italy **Department of Psychiatry and Psychology, “A. Gemelli” Hospital, Catholic University of the Sacred Heart, Rome, Italy

Abstract. – BACKGROUND: In this Part II feine, modafinil), hallucinogens (mescaline, LSD, psychiatric disorders coexisting with organic ecstasy) and other substances (cannabis, disso- diseases are discussed. ciatives, inhalants). Anxiety disorders can occur in “Comorbidity phenomenon” defines the not intoxication by stimulants, as well as in withdrawal univocal interrelation between medical illnesses syndrome, both by stimulants and sedatives. Sub- and psychiatric disorders, each other negatively stance induced mood disorders and psychotic influencing morbidity and mortality. Most severe symptoms are as much frequent conditions in ED, psychiatric disorders, such as schizophrenia, and the recognition of associated organic symp- bipolar disorder and depression, show increased toms may allow to achieve diagnosis. Finally, psy- prevalence of cardiovascular disease, related to chiatric and organic symptoms may be caused by poverty, use of psychotropic medication, and prescription and doping medications, either as a higher rate of preventable risk factors such as direct effect or after withdrawal. Adverse drug reac- smoking, addiction, poor diet and lack of exercise. tions can be divided in type A, dose dependent and Moreover, psychiatric and organic disorders can predictable, including psychotropic drugs and hor- develop together in different conditions of toxic mones; and type B, dose independent and unpre- substance and prescription drug use or abuse, es- dictable, usually including non psychotropic pecially in the emergency setting population. Dif- drugs, more commonly included being cardiovas- ferent combinations with mutual interaction of psy- cular, antibiotics, anti-inflammatory and antineo- chiatric disorders and substance use disorders are plastic medications. defined by the so called “dual diagnosis”. The hy- potheses that attempt to explain the psychiatric Key Words: disorders and substance abuse relationship are Psychiatric emergencies, Anxiety disorders, Mood examined: (1) common risk factors; (2) psychiatric disorders, Psychosis, Comorbidity, Dual diagnosis, disorders precipitated by substance use; (3) psy- Substance abuse, Drug abuse, Substance addiction, chiatric disorders precipitating substance use Drug adverse reactions. (self-medication hypothesis); and (4) synergistic interaction. Diagnostic and therapeutic difficulty concerning the problem of dual diagnosis, and le- Abbreviations gal implications, are also discussed. ACE = angiotensin-converting enzyme Substance induced psychiatric and organic symptoms can occur both in the intoxication and ADHD = attention deficit hyperactivity disorder withdrawal state. Since ancient history, humans se- CNS = central nervous system lected indigene psychotropic plants for recreation- COPD = chronic obstructive pulmonary disease al, medicinal, doping or spiritual purpose. After the CNS = central nervous system isolation of active principles or their chemical syn- ECG = electrocardiogram thesis, higher blood concentrations reached pre- ED = emergency department dispose to substance use, abuse and dependence. EEG = electroencephalogram Abuse substances have specific molecular targets GABA = gamma amino butyric acid and very different acute mechanisms of action, GHB = gamma hydroxybutyrate mainly involving dopaminergic and serotoninergic GnRH = gonadotropin releasing hormone systems, but finally converging on the brain’s re- GCS = Glasgow coma scale ward pathways, increasing dopamine in nucleus HIV/AIDS = human immunodeficiency virus/acquired accumbens. The most common substances pro- immune-deficiency syndrome ducing an addiction status may be assembled in ICU = intensive care unit depressants (alcohol, benzodiazepines, opiates), IFN = interferon stimulants (cocaine, amphetamines, nicotine, caf- LSD = lysergic acid

Corresponding Author: Americo Testa, MD; e-mail: [email protected] 65 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

MAOI = momoamino oxidase inhibitor The patient with psychiatric disorder who MDMA = 3,4-methylenedioxy-N-methylamphetamine complains medical illness is disconcerted in re- MR = magnetic resonance lating his symptoms. Both the patient and the NMDA = N-methyl-D-aspartate (receptor) NRI = noradrenalin reuptake inhibitor physician have great effort in diagnosing them as NSAID = non steroidal anti-inflammatory drug “real” or “unreal” symptoms. Most psychiatric PTSD = post-traumatic stress disorder disorders, such as schizophrenia, bipolar disorder SNRI = selective serotonin/norepinephrine reuptake and depression, are associated with undue med- inhibitor ical morbidity and mortality. It represents a ma- SSRI = selective serotonin reuptake inhibitor jor health problem, with up to 30 year shorter THC = delta-9-tetrahydrocannabinol lifetime compared with the general population, VTA = ventral tegmental area primarily due to premature cardiovascular dis- ease. The causes of increased metabolic and car- Introduction diovascular disease in this population are strong- ly related to poverty and limited access to med- The independent coexistence of psychiatric ical care, but also to the use of psychotropic and organic disorders in the same patient results medication. Moreover, the patients with severe in the well known “comorbidity phenomenon”. It mental illness have a higher rate of preventable defines the controversial interrelation between risk factors such as smoking, addiction, poor diet psychiatric disorders and organic diseases, each and lack of exercise3. Anxiety and post-traumatic other negatively influencing morbidity and mor- stress disorder (PTSD) seem to be interrelated tality. Indeed, concurrent or lifetime comorbidity with heart diseases in quite a similar way, con- phenomenon ranges from casual occurrence of tributing even more negatively to critical cardio- psychiatric disorders and medical diseases, to the logic events than depression. The prevalence actual susceptibility of psychiatric patients to rates of depressive disorders in various cardiolog- contract organic diseases, and vice versa. ic conditions are significantly higher than the fre- Co-occurrence and mutual interaction of psychi- quencies that can be expected in healthy general atric disorders and/or medical illness and substance population4. A complex relationship is known or drug abuse may also develop, causing diagnostic even between psychiatric disorders and respira- and therapeutic difficulty and significant legal im- tory illnesses. Moreover, anxiety, depression and plications1. Therefore, findings can vary depending psychosis are considered significant causes of on factors such as type of psychiatric and organic morbidity and mortality in patients suffering disorders and substance involved, making it neces- from COPD and asthma. Within gastroenterolog- sary to differentiate whether clinical symptoms are ical diseases, mental illness and psychosomatic primary, independent, or substance-induced, thus disorders have a main role either in therapy man- transient and treatable. agement or in patients quality of life, through the disease perception and its symptoms. Psychiatric patients are at high risk even for hepatic illness- Co-morbidity of Psychiatric Disorders, es: because the diffuse substances abuse and ad- Medical Diseases and Substance Abuse diction, they are more exposed to alcohol dam- age and infections by hepatic viruses and HIV. Co-occurrence of Psychiatric Disorders There is evidence that the association of mellitus and Medical Diseases diabetes and psychosis makes worse the progno- An alternative approach to “categorial” classi- sis both of psychiatric disorder and the metabolic fication (DMS IV-TR and ICD-10) for definition disease. In the end, a mention deserves even an- of psychiatric disorders consists in the “dimen- tipsychotics because these drugs have a complex sional” approach. This is based on the possibility way of action and can manifest interactions with that many psychiatric disorders present in a other drugs employed in different internal dis- vague or episodic form, without satisfying the eases and cause different side effects5. criteria for “categorical” disorders (so called sub- Otherwise, a patient with severe medical ill- threshold disorders). The dimensional approach ness complaining psychiatric symptoms chal- allows to detect minor but clinically meaningful lenges in depicting their independent nature, or symptoms and adjust therapeutic approach, as in- attributing a reactive significance (somatopsychic tegration of pharmacological and psycho-social disorders), or recognizing the occurrence of drug approach, in proportion to its relevance2. side effects. Emergence anxiety, depression,

66 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases delirium and other acute psychotic manifesta- Etiopathogenetic Mechanisms tions affecting postoperative and ICU patients, Several hypotheses have been advanced to ex- cancer and HIV/AIDS patients, particularly el- plain the relationship between psychiatric disor- derly or adolescent patients, were discussed in ders and substance abuse (dual diagnosis), ex- Part I review. ceeding the simple concept of the independent coexistence: (1) common factors (risk factors common to both disorders); (2) secondary psy- Co-occurrence of Psychiatric Disorders chiatric disorder (substance use precipitates and Substance Abuse: the “Dual Diagnosis” psychiatric disorder); (3) secondary substance use (self-medication hypothesis); and (4) bidi- Definition and Epidemiology rectional or synergistic interaction (presence of Concurrent or lifetime co-morbidity of toxic either psychiatric disorder or substance use dis- substance abuse (alcohol, heroin, cocaine etc.) order can contribute to the development of the and psychiatric disorders is high and subject of other)7,12. Firstly, individuals having a psychi- heated debate, without univocal conclusions on atric disorder also may manifest biological vul- relative responsibilities (“what came first, the nerability, caused by genetic and early stressful chicken or the egg?”), concerning the well- events. There is also evidence that social, eco- known “dual diagnosis” 6,7. Indeed, this subset of nomic, familial problems or traumatic life pathologies present complex and particular fea- events can lead to both psychiatric disorders and tures, due to the different combination of psychi- substance abuse. Then, several evidences sup- atric problems, ranging from casual coexistence port a causal link between substance abuse, to causal relationship. Associations have also such as alcohol and cannabis, and later develop- been found in the opposite direction, but retro- ment of obsessive compulsive disorder and psy- spective and prospective studies both indicate chosis, respectively. Bipolar disorder and anxi- that psychiatric disorders have a temporally pri- ety disorder also increased simultaneously with mary age of onset in the majority of dual diagno- recent significant increase in cannabis use in sis cases. Although the full impact of primary Western Countries13. Moreover, patients com- psychiatric disorder is unknown, simulation stud- plaining psychiatric symptoms could be incline ies have estimated that their early treatment or to misuse or abuse substances in order to relieve prevention might reduce up to 40% of cases of their psychic (anxiety, depression) or somatic secondary substance dependence8. Effectively, in symptoms (insomnia, pain), and counter the Western Countries the chances of lifetime devel- negative side-effects of antipsychotics adverse oping a substance abuse is significantly higher effects, in line with the self-medication hypothe- among patients with a pre-existing primary psy- sis14. Anxiety and unipolar mood disorders are chiatric disorder, ranging from 21 and 72%, than associated with later onsets of substance use in the general population without a psychiatric disorders. In particular, social anxiety disorder illness6. There is a statistically significant pre- predicts onset of alcohol use disorders, and dominance of men, as well as a younger age. The PTSD predicts the onset of all substance use substances most frequently used in dual diagno- disorders13. So, substances are not randomly sis group are alcohol (78.1%), cannabis (62.5%), chosen, but are specifically selected for their ef- and cocaine (51.6%)9. On the other hand, a num- fects. Some studies show that nicotine adminis- ber of studies report a high prevalence of psychi- tration can be effective for reducing motor side- atric disorders, namely mood and psychotic dis- effects of antipsychotics15. On the other hand, orders, among heroin abusers (up to 90%), while exposure to psychiatric medication is suggested anxiety, including PTSD, mood disorders and an- to produce biochemical and anatomical alter- tisocial personality disorder prevail among co- ations on CNS, potentially predisposing to toxic caine abusers (about 50%). Finally, depression substance abuse. and anxiety disorders, namely panic, social anxi- ety and obsessive compulsive personality disor- Diagnostic and Therapeutic Concerns ders, prevail among alcohol abusers (over Newly emerging psychiatric symptoms in the 50%)6,10,11. Recent studies have confirmed causal presence of substance abuse (or withdrawal) relationship between major psychiatric disorders should be presumed to be “substance induced” and concomitant substance abuse in 50-80% of until proven otherwise. Formally, in each case of forensic cases1. co-morbidity, a psychiatric disorder should be di-

67 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini agnosed as independent only if its onset precedes tilled wine dates about 1100 A.D., wine and alco- the substance assumption, if it is not linked to its holic spirits being taken as an universal medicine. recent assumption (<1 month), if continues >1 In an evolutionary theory, psychotropic plants month after its withdrawal. Although maybe its evolved to emit allelochemical reactivity to deter detection could be less complicated, it is usually threats from herbivores. These allelochemical re- easy to detect the abuse condition from history or sponses evolved to imitate mammalian neurotrans- from physical examination and toxicological tests. mitters. The fit of allelochemicals within the CNS Atypical antipsychotics are commonly used for indicates some coevolutionary activity between concomitant schizophrenia and substance abuse. mammalian brains and psychotropic plants, mean- Whereas there is no difference between risperidone ing they interacted ecologically and therefore re- and olanzapine, clozapine appears to have a distinct sponded to one another evolutionarily. advantage in reducing psychotic symptoms as well These natural neurotransmitters analogues were as substance abuse (including smoking). There is not anciently so plentiful and potent to cause se- emerging evidence that quetiapine is beneficial in vere intoxication or to produce dependence. In dually diagnosed patients, particularly using alco- modern era, isolation in pure form or chemical hol, cocaine and amphetamine. A combination of synthesis of active principles allowed their as- naltrexone and sertraline was found to be effective sumption in high doses, often intravenous, easily in patients with depressive disorder and alcohol de- predisposing to abuse and addiction17. pendence. Integrated intervention is the choice of Frequently, toxic substance abuse is combined, treatment for patients with dual diagnosis16. and the physician must consider this occurrence be- cause each substance may require specific treatment. Studies show up to 20% of alcohol-dependent indi- Substance and Drug Induced Psychiatric viduals having problems of dependence and/or mis- and Organic Symptoms use of benzodiazepines. Alcohol is cross-tolerant with other sedative-hypnotics, increasing craving for General Concepts benzodiazepines, but their combined assumption Substance or drug abuse, or their withdrawal, produces summarized life-threatening depressant ef- can produce both psychiatric and organic symp- fects (see below). Another common combination is toms, due to the damage on CNS, and gastroen- represented by cocaine and heroin assumption teric, cardiovascular and endocrine systems other (speedball), with the aim to enhance euphoric ef- than the developing of deficiency states. fects, to reduce withdrawal opiate symptoms, and to modulate irritability induced by cocaine. Benzodi- Historical Overview azepines often are associated to methadone for in- Since the beginning of the world each society creasing the excitement state. Alternatively, habitual has selected natural substances that distorted the cocaine and opiates users can assume benzodi- perception, mood or thought, for recreational, med- azepines to mitigate anxiety symptoms, which occur ical, military or spiritual purpose. In the Odyssey during assumption or withdrawal, respectively. Ex- by Homer (Book IV), Helena “drugged the wine perimental studies demonstrated that adaptation of with an herb that banishes all care, sorrow, and ill the adenylate cyclase system following toluene re- humour.” In popular comic books, Asterix’s “mag- peated inhalation might be involved in the expres- ic potion” or Popeye’s “spinach can” represent a sion of behavioural sensitization to subsequent masked version of doping usage. Australian and methamphetamine administration. American aborigines used nicotine from their in- digenous plants. Ethiopians and northern Africans Main Psychiatric and Organic Symptoms were documented as having used an ephedrine- Secondary to Substance and Drug Abuse analogue from Catha edulis. Since Neolithic Era, Anxiety disorders are common in intoxication people have cultivated and consumed Cannabis by stimulants (cocaine, crack, amphetamines, ec- sativa and Papaver somniferum in Asian and Euro- stasy), and uncommon in intoxication by seda- pean Countries, and Erythroxylum coca in the tives (opiates), except for alcohol. A paradoxical western Andes. Mescaline, alkaloid extracted from effect to benzodiazepines can occur, especially in the Peyote cactus, was used for its psychedelic elderly, producing anxiety manifestations. On the properties in religious ceremonies by Mexican na- other hand, anxiety disorders commonly occur in tives. Finally, alcoholic beverages have been pro- withdrawal syndrome, both by sedatives (opiates, duced already in a remote past. The recipe for dis- benzodiazepines) and by stimulants. The with-

68 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases drawal syndrome is due to: (1) substance with- hibitor systems. By high doses, sedative effects drawn; (2) re-bound effect with hyperactivation of prevail with recent memory disorders (black out CNS; and 3) re-emergence of underlying anxiety phenomenon) and potential development toward disorder. Typical manifestation in any case are coma and death. The alcohol dependence syn- restlessness, psycho-motor agitation, craving till drome (“alcoholism” in the past) presents a aggressive behaviours, generally associated to prevalence of 5-10% in West Countries, and is clear vegetative manifestations (insomnia, tachy- considered “the big simulator”, for multiform in- cardia, hypertension, sweating, nausea). In cases dividual clinical picture and its relation to blood of suspected substance induced mood disorders, it levels. Anxiety symptoms may occur both in is important to understand that many common or- acute and chronic alcohol intoxication, associat- ganic symptoms of depression (e.g., fatigue, sleep ed to sadness and depressive signs of CNS. In changes, gastrointestinal problems) can arise as withdrawal syndrome, anxiety symptoms are adverse effects of medications. Drugs with evi- common (> 50% of cases), begin within 24 h dence of a link to depression include IFN-alpha, from alcohol withdrawal, and combine with veg- corticosteroids and digoxin. Likewise, many etative symptoms (insomnia, hypertension, symptoms of mania (e.g., inattention, insomnia, tachycardia, sweating), tremor, restlessness, con- excess motor movements) may occur as adverse fusion state, visual hallucinations, seizures, till drug reactions, such as antidepressants. The tem- evolving toward the dramatic picture of “deliri- poral relationship between use or withdrawal um tremens”. This is a life-threatening condition from the medication and the mood symptoms is if associated to infective, metabolic or traumatic crucial to formulate this diagnosis18,19. Substances comorbidities. Habitual consumers develop toler- with psychomimetic properties such as cocaine, ance, and consequently physical dependence: to amphetamines, hallucinogens and cannabis are avoid withdrawal symptoms often they drink al- widespread, and their use or abuse can provoke cohol in the night and in the morning, to main- psychotic reactions resembling a primary psy- tain high serum concentration22. chotic disease, or disclose latent schizophrenia. Despite to their large prescription to treat anxi- The recent escalating use of methamphetamine ety disorders and insomnia, benzodiazepines throughout the world and its association with psy- rarely constitute abuse substance, except for mul- chotic symptoms in regular users has fuelled con- ti-substance abuse disorders. Pharmacological tol- cerns. Dependence upon and withdrawal from erance to their sedative action develop after sever- sedative hypnotics can be medically severe and, al weeks of assumption, while the tolerance to as with alcohol withdrawal, there is a risk of psy- anxiolytic and other effects is controversial. Ben- chosis other than seizures if not managed proper- zodiazepines acute intoxication can precipitate ly19,20. Some studies suggest that only alcohol, an- respiratory function (apnoea), which is enhanced tidepressants, benzodiazepines and cocaine are by alcohol and opiates co-assumption and by pre- related to aggressive behaviour. Aggression as an existing pulmonary disease. Other common ad- adverse cannabis reaction is very rare and occurs verse effects in acute and chronic intoxication in most cases in association with other drugs and consist in asthenia, loss of muscle coordination, in predisposed individuals. anterograd amnesia, headache, emesis, diarrhoea, dimming of the eyesight, articular and chest pain. Toxic Substances Rare paradoxical psychiatric manifestations may Substances of abuse have specific molecular occur during benzodiazepine use or abuse, the so targets and very different acute mechanisms of called “disinhibition reaction”. So, anxiety, eu- action, but at the end they converge on the phoria, irritability, hypomaniacal and aggressive brain’s reward pathways, increasing dopamine in behaviour, or depression and suicidal ideation, nucleus accumbens, so producing a series of and hallucinations may coexist with talkativeness, common functional effects after both acute and tachycardia and sweating. Prolonged use of ben- chronic administration (Table I)21. zodiazepines may produce somnolence, memory impairment, and daytime drowsiness. Moreover it Depressants may cause falls resulting in hip fractures and may The alcohol (ethanol) intake induces sedation result in motor vehicle accidents. Not severe, but and sleep. Low doses of alcohol produce com- prolonged withdrawal syndrome generally occurs fortable sensation, with talkativeness and excita- after benzodiazepine interruption in abusers, more tion, due to selective suppression of cerebral in- than regular prescriptional users. The clinical pic-

69 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

Table I. Main classes of commonly abused substances, their main specific molecular targets, and some of their mechanism by which they activate the dopaminergic and serotonergic systems, leading to increase dopamine in nucleus accumbens.

Drug Target Mechanism

Depressants Alcohol, benzodiazepines Multiple targets, including GABA Facilitate GABAergic neurotransmission, and barbiturates and glutamate receptors which may disinhibit VTA dopamine neurons from GABA interneurons or may inhibit glutamate terminals that regulate dopamine release in nucleus accumbens. Opiates(morphine, µ-opioid receptor Disinhibit neurons of the mesolimbic dopamine codeine and heroin) pathway by inhibiting GABA interneurons, that contain µ-opioid receptors in the ventral tegmental area, or directly activate nucleus accumbens neurons that contain µ-opioid receptor. Stimulants Cocaine, amphetamine, Dopamine transporter Block dopamine transporter on the terminals of methamphetamine dopamine projecting neurons of the mesolimbic or ecstasy dopamine pathway (cocaine, crack), or release dopamine from the vesicles of dopamine terminals (amphetamine, methamphetamine). Nicotine Nicotinic receptors Directly activates neurons of the mesolimbic dopamine (predominantly 4 2 subtype) pathway by stimulating their nicotine receptors, and α β indirectly activates them by stimulating the nicotine receptors in glutamatergic terminals to ventral tegmental area dopamine neurons. Caffeine Adenosine receptors Inhibits adenosine A2A receptors interaction with (predominantly A2A subtype) dopaminergic transmission in the striatal GABAergic neurons projecting to the ventral pallidum, so decreasing GABA release in the nucleus accumbens. Eugeroics Multiple targets, including Induce wakefulness by its action in the anterior (modafinil, adrafinil, orexin trasmission, hypothalamus, activating orexin neurons, which and ampakines) α1-adrenergic and project to the entire CNS. Facilitate excitatory glutamate receptors glutamatergic signalling and also amplify midbrain noradrenergic signals, cortical serotonin release and extracellular levels of dopamine, including the nucleus accumbens. Hallucinogens Mescaline, psilocybin, Serotonin receptors Enhance glutamatergic transmission in the cerebral LSD, ecstasy cortex, responsible for the higher-level cognitive, perceptual, and affective distortions produced by these drugs, acting on serotonin receptors. The coeruleo- cortical noradrenergic system and the cerebral cortex are among the regions where hallucinogens have prominent effects. Other substances Cannabinoids Cannabinoid CB1 and Regulate dopaminergic signalling through CB1 and (marijhuana, hashish) CB2 receptors CB2 receptors in nucleus accumbens neurons and in GABA and glutamate terminals to nucleus accumbens Club Drugs o NMDA receptors Ketamine binds to the NMDA receptor, blocking dissociatives (ketamine, (by ketamine) calcium flow and increasing dopamine release in gamma-hydroxybutyrate GHB receptors prefrontal cortex and midbrain. NMDA blockade has o GHB) (by gamma-hydroxybutyrate) also been linked to activation of serotonin systems. GHB receptors have the highest density in the hippocampus, cortex, and dopaminergic areas (striatum, olfactory tracts, and substantia nigra). GHB acts increasing central dopamine levels, which could be associated with the reinforcing effects of GHB. Inhalants or volatile solvents Multiple targets, including GABA Their anxiolytic effects depend on their positive (toluene, benzene, chloroform, receptors (predominantly modulation of GABA receptors. Induce subjective xylene, acetone, alkyl nitrites, GABAA subtype) and psychedelic effects blocking NMDA receptors. butane, benzene, nitrous NMDA receptors Increase dopamine levels in the prefrontal cortex, oxide, chlorofluorocarbons, (predominantly NR1 and striatum and VTA, so producing their halothane) NR2B subtypes) rewarding effects.

70 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases ture of withdrawal syndrome resembles alcohol yarrhythmia), muscular (tremor, abnormal invol- withdrawal one23. untary movements), thermoregulatory (increased Opiates (morphine, codeine and heroin) pro- body temperature), and respiratory systems duce analgesia acting on thalamus, sedation on (tachypnea, bronchospasm), can present as or reticular substance and euphoria on limbic sys- with acute neuropsychiatric symptoms. Indeed, tem, often described as intense pleasure like or- the complex manifestations of cocaine can pose gasm, associated to transient heat sensation with substantial problems in differential diagnoses and rush, followed by a period of sedation. As other resuscitative treatment (Figure 1)24,26. Chronic co- depressants, in heroin intoxication organic symp- caine use may be associated with deficits in neu- toms prevail on neuropsychiatric manifestations, ro-cognition, hallucinations and paranoid delu- with emesis, myosis, bradycardia, impairment of sions, irritability and violent behaviour. Tachycar- consciousness and breath, up to apnea and coma. dia and hypertension prevail among the organic Heroin consumers frequently present infections manifestations, with increasing risk for myocar- for the use of contaminated preparations and ex- dial infarction, aortic dissection, cerebral is- change of material per injection, with pneumo- chemia, rabdomyolysis and seizures, other than nia, cutaneous abscesses, phlebitis, endocarditis increased traumatic injuries. Premature delivery is and HIV infection. Opiates produce physical de- a common outcome in pregnant abusers18. Other pendence with an acute withdrawal syndrome organic adverse effects from chronic smoking of characterized by craving manifestations, hyper- cocaine include hemoptysis, itching, fever, diffuse estesia and hyperalgesia, insomnia, depression, alveolar infiltrates without effusions, asthma, pul- often preceded from anxiety symptoms and irri- monary and systemic eosinophilia, chest pain, tability. These behavioural and psychological sore throat, hoarse voice, and a flu-like syndrome. symptoms are associated to organic manifesta- Moreover, cocaine does often cause bruxism, tions, referable to the lost inhibition of locus which can deteriorate tooth enamel and lead to ceruleous neurons, such as emesis, diarrhoea, gingivitis. Chronic intranasal usage can degrade mydriasis, sweating, horripilation, cramps, tachy- the cartilage of the septum nasi, leading eventual- cardia, yawning, sometimes fever. Withdrawal ly to its complete disappearance. Finally, cocaine syndrome may be precipitated from antagonists may also greatly increase this risk of developing administration (naloxone or naltrexone) for over- connective tissue diseases (vasculitis). Cocaine dose treatment24. and amphetamines withdrawal syndrome (crash) is frequent in heavy users, when dependence had Stimulants begun. It is revealed by anxiety symptoms and de- Cocaine and its analogous (e.g. crack, in the pression, lethargy, asthenia and bradycardia. form of free base, easy to inhale if previously Urine titration of cocaine metabolites can detect warmed) show their pharmacological effects pri- its use up to 10 days after the last assumption25. marily on dopaminergic neurons in several areas Nicotine is the main active substance in ciga- of the brain, with inhibition of their re-uptake. rette smoking. It may be considered the first The evidence indicates that frontal lobe dysfunc- cause of morbidity and mortality in Western tion may be an important treatment target in co- Countries, other than the most common sub- caine use disorder. Amphetamines are similar to stance producing an addiction status. Deficit of cocaine, but they act mainly as peripheral and attention, irritability, craving, anxiety symptoms central adrenergic agonist, by increasing and depressed mood prevail among withdrawal presinaptic release of dopamine25. Acute and symptoms, being common behavioural and vege- chronic intoxication by these stimulants produces tative disturbances such as hostility, insomnia, anxiety symptoms, prevailing obsessive-compul- bradycardia and appetite increase27. The univer- sive disorder, panic attack and phobic disorders, sal appeal of caffeine, a xanthine derivative, as- depressive symptoms (anhedonia), and manifesta- sumed by beverages such as coffee, tea and cola, tions due to elevated mood, such as megalomania, is related to its mild psychostimulant properties. anger and violent behaviour. Psychosis may also Even though the primary action of caffeine may occur. Acute cocaine overdose is potentially be to block adenosine receptors, this leads to lethal, such as suicidal behaviours, violent psy- very important secondary effects on many classes choses, strokes, seizures and encephalopathy. Al- of neurotransmitters, including noradrenaline, so, cocaine’s toxic effects on the cardiovascular dopamine, serotonin, acetylcholine, glutamate, (hypertensive crisis, myocardial infarction, tach- and GABA. In a healthy person, caffeine pro-

71 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

Figure 1. ECG showing a tachycardia with wide QRS complex (Ventricular Tachycardia). Tachyarrhythmias may represent a cardiovascular complication of cocaine and other stimulants overdose in ED. motes cognitive arousal and fights fatigue, but plications, since the high potential for pharmaco- these same activating properties can produce kinetic interactions. Withdrawal symptoms con- symptomatic distress in a small subset of the sist of dysphoric mood changes, fatigue, muscle population, with 50% symptoms of nervousness, pain, stiffness, lethargy, headache and nausea, excitation, abdomen pain, dry mouth, tremor, with subjective psychological distress and signif- nausea, and jitteriness. Susceptibility to this icant impairment of psychomotor speed and cog- symptomatic distress is broadly determined by nitive performance tests29. three factors: the dose consumed, individual vul- nerability to caffeine, and pre-existing medical or Hallucinogens psychiatric conditions (mood disorders in partic- Hallucinogens (or psychedelics) psilocybin, ular) that are aggravated by mild psychostimulant mescaline, lysergic acid (LSD), and 3,4-methyl- use. The caffeine excess produces persisting in- enedioxy-N-methylamphetamine (MDMA, com- somnia, nervousness, and mood fluctuations. monly called ecstasy) produce perceptual disor- Symptoms of ADHD may be altered by caffeine ders and visual hallucinations. Their psychic ef- as well. Psychosis can be induced in normal indi- fects are referable to the affinity to the serotonin- viduals ingesting caffeine at toxic doses, and ergic receptors mainly on raphe neurons, which psychotic symptoms can also be worsened in tonically inhibit visual sensorial afferences. Re- schizophrenic patients using caffeine. Other cently, a serotonin receptor-mediated enhance- symptoms affecting the cardiovascular system ment of glutamatergic transmission in the cere- range from moderate increases in heart rate to bral cortex has been proposed as responsible for more severe cardiac arrhythmia28. A number of the higher-level cognitive, perceptual, and affec- drugs, including certain SSRIs, antipsychotics, tive distortions produced by these drugs. Panic at- antiarrhythmics, theophylline and quinolones, tack with agoraphobia is the most common anxi- have been reported to be potent inhibitors of cy- ety disturb in ED in abusers of LSD and ecstasy, tochrome P450, which participates in the metab- who experience a “bad trip”, often occurring in olism of caffeine. This has important clinical im- adolescents assuming the substance by soaked

72 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases stamps or by pills supplied in discotheque. Mood ports of synthetic cannabinoids adverse effects disorders, such as empathy and euphoria, or de- including tachycardia, hypertension, tachypnea, pression, and prolonged psychotic reaction are al- chest pain, heart palpitations, hallucinations, rac- so common30. Organic symptoms suggesting hal- ing thoughts, and seizures. While reports suggest lucinogens taking include mydriasis, tachycardia, that toxic symptoms last no longer than 3-4 hypertension, lacrimation, salivation (but dry hours, with no residual adverse effects in many mouth in ecstasy abuse), sweating and rush. Ec- cases, there is concern about serious acute and stasy can lead to acute, potentially lethal, toxicity long-term toxicities34. Coinciding with the in- (malignant hyperthermia and/or hepatitis), and creasing rates of cannabis abuse has been the neurotoxicity in the long-term, involving various recognition of a new clinical condition known as neurobiological systems (serotonin, dopamine, cannabinoid hyperemesis syndrome, character- noradrenalin), that may all interact31. ized by chronic cannabis use, cyclic episodes of nausea and vomiting, and frequent hot bathing. Other Substances Despite the well-established anti-emetic proper- Cannabis includes 61 cannabinoids having ties of marijuana, there is increasing evidence of slow elimination (up to 30 days), the psychoac- its paradoxical effects on the gastrointestinal tract tive agent being Delta-9-tetrahydrocannabinol and CNS. Cyclic vomiting syndrome shares sev- (THC). Cannabis flowers (marijuana) and prepa- eral similarities and the two conditions are often rations derived from resinous extract (hashish) confused35. Finally, Raynaud’s phenomenon, as are consumed by smoking, vaporizing and oral well as arteritis due to cannabis consumption ingestion, being estimated to be the most used il- may be extremely severe and result in worrying licit substance in USA. Their euphoric effects situations for both clinicians and patients36. (high and mellowing out) differ from opiates and The U.S. Office of National Drug Control Poli- other stimulants. Cannabis abuse can produce se- cy identifies four specific “club drugs” (also vere anxiety symptoms, mainly as panic attacks, known as “rave drugs” and “party drugs”): keta- more frequent in occasional users, and hallucina- mine, gamma hydroxybutyrate (GHB), ecstasy, tions, till acute psychosis. Minor symptoms from and flunitrazepam (Rohypnol). Ketamine is a de- smoking (bronchitis, sleep disturbances) may co- rivative of phencyclidine used in human, both in exist. A causal role of acute cannabis intoxication trauma and emergency surgery, and veterinary in motor vehicle and other accidents has now medicine, for its anaesthetic and analgesic proper- been shown by the presence of measurable levels ties. It induces a state referred to as “dissociative of THC in the blood of injured drivers in the ab- anaesthesia” and is used as a recreational drug. In sence of alcohol or other drugs. Chronic inflam- combination with psychiatric manifestations, such matory and precancerous changes in the airways as acute delirium, short term neurological adverse have been demonstrated in cannabis smokers. effects are reported in 40% of patients, e.g. dizzi- Several different studies indicate that the epi- ness, diplopia, blurred vision, nystagmus, altered demiological link between cannabis use and hearing37. Measurable changes in peripheral organ schizophrenia probably represents a causal role systems, including the cardiovascular, gastroin- of cannabis in precipitating the onset or relapse testinal, and respiratory systems, as referable to of schizophrenia. A weaker but significant link its effects on catecholaminergic transmission. In- between cannabis and depression has been found deed, ketamine inhibits reuptake of cate- in various cohort studies, but the nature of the cholamines, resulting in hypertension and tachy- link is not yet clear. A large body of evidence cardia, while stimulation of β2 adrenergic recep- now demonstrates that cannabis dependence, tors produces bronchodilation. Finally, inhibition both behavioural and physical, does occur in of neuronal uptake and increased serotonergic ac- about 7-10% of regular users, and that early on- tivity are thought to underlie nausea and vomit- set of use, and especially of weekly or daily use, ing. Long term side effects include neurological is a strong predictor of future dependence32. After abnormalities, with neurocognitive impairment, withdrawal in habitual users psychiatric and or- deficits in working and episodic memory, and uri- ganic symptoms may occur within 48 hours: irri- nary tract symptoms, which have been collective- tability and aggression, insomnia, restlessness, ly referred as ketamine-induced ulcerative anxiety, electroencephalographic alterations and cystitis38. Gamma-hydroxybutyric acid (GHB) is a nausea and cramps are described; symptoms sub- naturally occurring neurotransmitter in the brain, side within 2 to 12 weeks33. There are various re- structurally related to the neurotransmitters gam-

73 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini ma-aminobutyric acid (GABA) and glutamic thy) or loss of brain cells (cerebral atrophy), and acid, acting on dopaminergic systems, with only loss of muscle strength and coordination due to common medical applications in the treatment of damage to the cerebellum (cerebellar ataxia). narcolepsy. Like alcohol, it is a CNS depressant, Moreover, inhalants can cause chronic medical but at small doses can act as aphrodisiac and problems affecting multiple organ systems, so stimulant, inducing euphoria, disinhibition, and causing liver, heart, and kidney toxicity, bone dem- sociability. At higher doses, GHB may induce ineralization, bone marrow suppression, reduced nausea, vomiting, gastrointestinal tract irritation, immunity (T-cell response) and pulmonary dys- dizziness, depressed breathing, visual distur- function, injured alveolo-capillary membrane and bances, drowsiness, agitation, amnesia, uncon- predisposing with tuberculosis, bronchitis, asthma sciousness, and death. The effects of GHB can and sinusitis. Poppers, a slang term for various last from 1.5 to 3 hours, or even longer if large alkyl nitrites, can induce vertigo, headache, palpi- doses have been consumed39. GHB has also been tation, hypotension and temporary changes in vi- associated with a withdrawal syndrome of insom- sion. Despite to the negative indications of DSM- nia, anxiety, muscular cramping, tremor, perspira- IV, a recent study provides evidence for a lifetime tion, and bowel and bladder incontinence, that inhalant-related withdrawal syndrome in approxi- usually resolves in 3-12 days. The withdrawal mately 20% of inhalant abusers and 50% of those syndrome can be severe producing acute delirium with inhalant dependence. The most commonly re- and may require hospitalization in an ICU for ported withdrawal symptoms are hypersomnia, management40. feeling tired, and nausea. Other neuropsychiatric Inhalants (or volatile solvents) such as glues symptoms are hallucinations and restlessness, and adhesives (toluene, benzene, chloroform, which may coexist with vegetative and organic etc.), cleaning agents (tetrachloroethylene, manifestations, such as headache, sweating, tachy- trichloroethane, xylene), solvents (acetone, ethyl cardia, tremors muscular pain and fever41. acetate, alkyl nitrites), gases (butane, isopropane), aerosols (chlorofluorocarbons), gasoline (benzene, Medicaments xylene), and anaesthetics (nitrous oxide, halothane, Prescription medications are commonly respon- enflurane, desflurane, isoflurane, ethyl chloride), sible of psychiatric and organic symptoms. In pri- are very lipophilic molecules which when inhaled mary health care approximately 2% of patients re- produce changes in mental status, prevalently anal- ceiving pharmacotherapy develop side effects, gesia and euphoric-oniroide status. Inhalant use hence in hospitalised patients clinically relevant disorders are among the least prevalent and danger- side effects exceeds 10%. Additionally, it has been ous substance use disorders, their lifetime preva- estimated that approximately 3-5% of all hospital lence being estimated in about 10% among admissions are related to adverse drug reac- teenagers, up to 50% of whom may develop depen- tions42,43. Clinically relevant adverse drug reac- dence. Panic attack and generalized anxiety disor- tions concern most frequently the gastrointestinal der represent the most common adverse psychiatric tract, the haematological systems, the skin, the events associated to intoxication by inhalants, cardiovascular system, other than the CNS. Fac- which generally produces a syndrome similar to al- tors predisposing for clinically relevant adverse cohol intoxication, consisting of dizziness, slurred drug reactions are female gender, elderly and speech, euphoria, lethargy, slowed reflexes, slowed polypharmacy, with meanly 6 drugs administered thinking and movement, incoordination, tremor, per day in inhospital patients in Internal Medi- generalized muscle weakness, involuntary eye cine42. Depending on the development mecha- movement, blurred vision, stupor, coma and death. nism, psychiatric as well organic side effects can Inhalant intoxication also increases the risk for fa- be divided in two basic groups: type A side effects, tal injuries from motor vehicle or other accidents, characterized by the qualitatively standard, but and catastrophic medical emergencies such as ven- quantitative augmented pharmacologic effects, tricular arrhythmias, leading to “sudden sniffing dose dependent and predictable, including psy- death”. Recreational inhalant users, as occupation- chotropic drugs and hormones; type B side effects, al exposures, may present memory, attention, and unexpected considering the pharmacological fea- judgment deficits compared with controls. Recur- tures of the medication, and dose independent and rent inhalant intoxication can lead to neurological unpredictable, usually including non psychotropic disorders, including Parkinsonism, impaired cogni- drugs (e.g. cardiovascular, antibiotics, anti-inflam- tion due to degradation of brain cells (encephalopa- matory and antineoplastics) (Table II)43. The psy-

74 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases chiatric symptoms are often dose related, e.g. type Psychotropic Agents A side effects. Hence, age and slow speed of Psychoactive substances and medications are detoxification will increase the risk of patients de- commonly classified into four categories: tran- veloping sleep disturbances, anxiety, delirium, and quilizers, depressants, stimulants and hallucino- hallucinations43,44. Several medications (e.g., bar- gens, including the novel class of psychostimu- biturates, vigabatrin, topiramate, flunarizine, corti- lants eugeroics under which modafinil, adrafinil, costeroids, mefloquine, efavirenz, and IFN-alpha) and ampakine are categorized. However, the do appear to cause depression in some patients bounds of these categories are not precisely de- and should be used with caution in patients at risk lineated; rather, they have several effects that for depression. On the other hand, many other re- overlap or combine into a new, different one lationships are still controversial, such as the asso- (Figure 2)47. ciation of depression with sedatives, anti-hyper- The evidence suggests that although illegal tensive and oral contraceptives45. Sedative drugs drug use is relatively rare among older adults are those most commonly associated with psy- compared with younger adults and adolescents, chomotor impairment, and may include psy- there is a growing problem of the misuse and chotherapeutic drugs, sedative antihistamines and abuse of prescription drugs. Psychoactive med- narcotic analgesics. Delirious states are most often ications are used by at least 1 in 4 older adults, associated with drugs that possess central anti- and such use is likely to grow as the population cholinergic actions, including not only drugs ages. It is estimated that up to 11% of older clearly identified as anticholinergics, but also tri- women misuse prescription drugs49. cyclic antidepressants and anti-Parkinson drugs. Sedatives-hypnotics, such as benzodiazepines Cimetidine, which is often used parenterally in se- and barbiturates, are reported to have a significant riously ill patients, is also a prominent cause. The association with depression45,50. Nevertheless, toxic association of schizophrenic-like psychoses with influence of tricyclic antidepressants (e.g., dopaminomimetic drugs tends to support the pre- amitriptyline, imipramine, doxepin and trazodone) vailing dopamine hypothesis of schizophrenia. on CNS can result in confusion, memory disorder, Levodopa and bromocriptine are examples of such anxiety, irritability and agitation which diagnosti- relationships. Manic reactions are clinically diffi- cally should be differentiated from the increase of cult to differentiate from schizophrenic-like psy- depressive symptoms or relapse of depressive dis- choses and are often produced by similar drugs46. order. Organic symptoms and signs of antidepres- Psychiatric and organic symptoms can also occur sant toxicity, such as dry mouth, drowsiness, when drugs to which a patient has developed some weight gain, level of consciousness by GCS, con- measure of tolerance are abruptly withdrawn, es- vulsions, and QT and QRS prolongation, can be pecially psychotropic drugs. Medicaments more very helpful in differential diagnosis, as well as de- commonly producing coexistent psychiatric and termining their blood level43. Some patients that are organic adverse reactions are listed in Table III. A more than six months on selective serotonin reup- systematic classification according to their usual take inhibitors (SSRIs) fluoxetine, fluvoxamine, therapeutic use is presented, to facilitate a prompt paroxetine, sertraline, escitalopram, citalopram, or anamnestic recognition. on selective serotonin/norepinephrine reuptake in-

Table II. Comparison of features type A and type B side effects of medications.

Type A Type B (augmented pharmacologic effects) (unexpected reactions)

Pharmacologic predictable Yes No Dose dependent Yes No Medication number dependent Yes No Drug interactions dependent Yes No Incidence High Low Morbidity High Low Mortality Low High Treatment Appropriation of medication dose Discontinuation of medication

(From: Mihanovi M et al. Psychiatria Danubina, 2009)43.

75 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

Table III. Most common prescription and illicit medications causing psychiatric and somatic symptoms, as direct effect or for their withdrawl. A systematic classification according to their usual therapeutic use is presented, to facilitate a prompt anamnestic recognition.

Psychiatric drugs Scopolamine Cycloserine Benzodiazepines H2-histamine blockers Terizidone Barbiturates Pantoprazole Oseltamivir Antipsychotics Efavirenz Tryciclic antidepressants Hormones SSRI/SNRI antidepressants L-thyroxine Immunosoppressors and NRIs Progestinics immunomodulators Atomoxetine GnRH agonists Corticosteroids Oral contraceptives Interferon-Alpha Neurological drugs Finasteride Interleukin-2 MAOIs Anabolic-androgenic steroids Cyclosporine Anticholinergic Tacrolimus L-dopa Dermatologic drugs Dopaminergic H1-antihistaminics Antineoplastics Antiepileptics Isotretinoin Methotrexate H1-antihistaminics Vincristine Triptans Analgesics and Ifosfamide Melatonin antinflammatory drugs Cyclosporine Opioid analgesics Fludarabine Cardiovascular drugs NSAIDs Cytarabine Digoxin Corticosteroids 5-fluorouracil Clonidine Cisplatin Methyldopa Antibiotics, antimalarials, L-asparaginase Beta-blockers antituberculosis and Paclitaxel ACE-inhibitors antiviral agents Doxorubicin Angiotensin-II blockers Sulfonamides Cyclophosphamide Calcium channel blockers Quinolones Diuretis Clarithromycin Doping agents Statins Amoxicillin Psychostimulants Linezolid Modafinil Respiratory drugs Cephalexin GHB Corticosteroids Metronidazole Anabolic-androgenic steroids Destrometorphan Chloroquine Beta2-agonists Mefloquine Diuretics Gastroenterologic drugs Isoniazid Corticosteroids Metoclopramide Ethionamide Beta-blockers hibitor (SNRIs) venlafaxine and duloxetine, can severity of the discontinuation syndrome is linked develop symptoms such as apathy, lack of motiva- with half-life of drug, paroxetine. Paroxetine and tion and emotional blunt presented as inability to venlafaxine, whose half-lives are shorter, are main- cry, frequently associated to sexual dysfunctioning, ly involved. Most of the discontinuation symptoms sleepiness, and weight gain. These psychopatho- are physical (flu-like, symptoms, myalgia and ab- logic symptoms should be distinguished from the dominal discomfort) and misdiagnosis can also symptoms of primary depressive disorder, and clin- lead to unnecessary investigations or to inappropri- ical experience shows that these symptoms tend to ate treatment. Bupropion, an atypical antidepres- reduce after discontinuation of SSRIs or after ad- sant also effective in smoking cessation, is struc- ministration of dopamine agonists such as atypical turally similar to diethylpropion, an appetite sup- antidepressant bupropion. SSRI citalopram, esci- pressant, showing poor selective noradrenergic ef- talopram, and fluoxetine are associated with hy- fects. Its dopaminergic action is thought to play a ponatraemia an increased risk of stroke. A fatal role in the pathophysiology of acute delirium de- serotonin syndrome has been described, especially scribed during its therapeutic use. The most serious in combination with triptans, characterized by hy- adverse effect of bupropion is seizure, which af- perthermia, mental status changes, restlessness, fects an estimated 1 in 1000 users, while more myoclonus, hyperreflexia, diaphoresis, or evidence common side effects include dry mouth, insomnia, of autonomic hyperactivity43,51. The frequency and skin rash and pruritus52.

76 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases

Substances: 9 Inhalants 15 NRIs (bupropion, methylphenidate) 1 Amphetamines 10 Ecstasy 16 MAOIs 2 Cocaine 11 Cannabis 17 Benzodiazepines 3 Caffeine 12 Hallucinogens (mescaline, LSD) 18 Barbiturates 4 Nicotine 13 Eugeroics (modafinil, adrafinil, 19 Anticholinergics (atropine, scopolamine) 5 Alcohol ampakines) 20 Typical tranquillizers (haloperidol) 6 Opiates 21 Atypical tranquillizers (sulpiride, 7 Opioid-like drugs (dextromethorphan Medications: clozapine) 8 Dissociatives (ketamine, GHB) 14 SSRIs/SNRIs 22 Selective NRIs (atomoxetine)

Figure 2. Classification of prescriptional and illicit psychoactive drugs, and their overlapping (modified from: Kim D. Envi- ron Health Toxicol, 2012)47. The reference numbers arrange themselves in a “fish shape” crossing the 4 circles, an effective mnemonic device. Hence, fish represents a traditional source of vitamins, whose healing properties are told since in Bible, and a modern healthful food rich in omega-3 fatty acids. Its antidepressant properties, by a regular intake of cod liver oil, has been recently reported48.

Methylphenidate, a derivative of amphetamine, adverse events included headache, abdominal is a stimulant effective for the treatment of atten- pain, decreased appetite, vomiting, somnolence, tion-deficit/hyperactivity disorder (ADHD). Its and nausea, with a significantly higher incidence use includes adverse cardiac effects, such as a of suicidal ideation than placebo54. modest rise in blood pressure and heart rate, ap- Anticholinergic drugs for treating neurological petite suppression, and negative emotional symp- (Parkinson’s disease), respiratory (asthma), gas- toms and psychotic episodes53. Atomoxetine is troenterological (spastic manifestations) and uro- a selective noradrenaline reuptake inhibitor logical (overactive bladder) diseases, and tryciclic (NRI) that is not classified as a stimulant, and al- antidepressants and antipsychotics such as chlor- so indicated for use in patients with ADHD. It is promazine, clozapine and olanzapine with anti- particularly useful for patients at risk of sub- cholinergic features, can induce delirium. Coexis- stance abuse, as well as those who have co-mor- tence with confusion, disorientation, tactile and vi- bid anxiety or tics. The mechanism of action of sual hallucinations together with typical antimus- atomoxetine is unclear, but is thought to be relat- carinic adverse reactions, such as the headache, ed to its selective inhibition of presynaptic nora- blurred vision with mydriasis, tachycardia, dry drenaline reuptake in the prefrontal cortex. Ato- mouth, constipation and urine retention, and infor- moxetine is generally associated with increases mation about taking anticholinergics indicate that in both heart rate and blood pressure. Common it is most probably anticholinergic delirium43.

77 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

Fever may develop in childhood, while cardiac ar- Changes in transmitter balance and receptor rhythmias constitute less common but potentially excitability are the main causes of the type A tox- life-threatening adverse reactions, due to pro- ic side-effects of L-dopa. Confusion and acute longed QTc interval. They occur only in the pres- psychosis may occur with peripheral gastroen- ence of multiple additional risk factors, such as teric (nausea) and cardiac symptoms (hypoten- age over 65 years, bradycardia, hypokalemia, hy- sion), other than with more usual dyskinesic pomagnesemia, supratherapeutic or toxic serum manifestations, while a malign neuroleptic syn- concentration, or interference with drug metabo- drome is described after its withdrawal. Sec- lism. The ECG and electrolytes should be taken in ondary psychosis was recognized in 1.3% of pa- account in ED patients taking psychotropic drugs, tients treated with therapeutic dosages of the and pre-existing cardiovascular disease or simulta- dopamine agonist drugs bromocriptine, cabergo- neous administration of other drugs delaying repo- line and lisuride, also used for treating function- larization carefully investigated55. ing pituitary tumours. Symptoms included audi- Finally, serotonin syndrome and neuroleptic tory hallucinations, delusional ideas, and appre- malignant syndrome are uncommon but poten- ciable changes in mood58. tially life-threatening adverse reactions associat- A significant increase in suicidal attempts re- ed with psychotropic medications, often com- sults in patients taking antiepileptic drugs, partic- bined, in which neuropsychiatric and organic ularly when the individuals had a preexisting his- symptoms may co-occur. Both conditions present tory of depression59. Several data reveal evidence as mental status changes, autonomic nervous sys- for both positive and negative effects on anxiety, tem disturbances, neurologic manifestations, and aggression, sleep, depression and psychosis in hyperthermia or hyperpirexia. However, the ele- patients with epilepsy. Topiramate, vigabatrin, vation in creatine kinase, liver function tests (lac- levetiracetam, tiagabine and zonisamide have tate dehydrogenase, aspartate transaminase), and been associated primarily with adverse psy- white blood cell count, coupled with a low serum chotropic effects, especially depression, that may iron level, distinguishes neuroleptic malignant be often under-diagnosed, and psychosis45. syndrome, for which dantrolene is the effective Gabapentin withdrawal can occur at doses rang- evidence-based drug treatment, from serotonin ing from 400-8000 mg/day for as little as 3 syndrome, for which only supportive care is indi- weeks. Patients can experience restlessness, dis- cated, among patients taking neuroleptic and orientation, confusion, agitation, anxiety, confu- serotonin agonist medications simultaneously56. sion, headache and light sensitivity60. Cinnarizine and flunarizine are piperazine deriv- Neurological Drugs atives with H1-antihistamine properties and calci- Notselective monoamine oxidase inhibitors um channel blocking activity. They are effective in (MAOIs) phenelzine, tranylcypromine, isocarbox- the prophylaxis of migraine, occlusive peripheral azid, and selective inhibitors for MAO-B selegiline vascular disease, vertigo of central and peripheral and rasagiline, are clinically used to treat Parkin- origin, and as an adjuvant in the therapy of epilepsy. son’s disease by blocking the degradation of neu- Several reports have described extrapyramidal reac- roactive catecholamines. In depression, their usage tions and depression associated with their use61. is now limited to refractory cases, because of their Triptans (sumatriptan, zolmitriptan, rizatriptan, negative side effects. Inhibition of other enzymes, naratriptan, almotriptan, eletriptan and frovatriptan) such as the drug-metabolizing cytochromes P450 are effective in the treatment for acute attacks of with food and drug interactions, is responsible of migraine, showing associated adverse events simi- tyramine-induced hypertensive crisis (e.g., the lar to placebo. They include dizziness, somnolence, “cheese reaction”). Therapy with new MAOIs ap- asthenia, and chest tightness62. However, alert pears to be associated with a low incidence of cog- should be warned about the potential life-threaten- nitive and behavioural adverse events. Nervousness ing risk of serotonin syndrome when triptans are may occur, but a potentially lethal serotonin syn- used in combination with selective serotonin reup- drome has been reported. Vegetative and organic take inhibitors (SSRIs) or selective serotonin/norep- symptoms more commonly associated in MAOIs inephrine reuptake inhibitors (SNRIs). toxicity are sleep disorders, dizziness, muscle pain, The interest on melatonin for the prevention paresthesias, edema, orthostatic hypotension, dry and treatment of jet lag and insomnia has in- mouth, diarrhoea, sexual dysfunctions, difficulty creased a lot in the last decade. This is mainly urinating, and hepatotoxicity57. due to its safety and its lack of serious adverse

78 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases reactions. Indeed, neuropsychiatric adverse reac- pected drugs responsible for serious psychiatric tions were prevalently described, including con- adverse reactions in paediatric population, other fusion due to melatonin overdose, fragmented than central simpaticomimetic drugs67. Mon- sleep, a psychotic episode, optic neuropathy, telukast is a potent leukotriene-receptor antago- nistagmus, seizures and headache. Autoimmune nist used in the treatment of asthma and allergic hepatitis and skin eruptions also occurred63. rhinitis. Psychiatric disorders reported include nightmares, unspecified anxiety, aggressiveness, Cardiovascular Drugs sleep disorders, irritability, hallucination, hyper- A number of psychiatric effects, including activity, and personality disorder68. Cough sup- mood syndromes, psychosis, and cognitive distur- pressant destrometorphan, a typical morphine- bances, have been reported in patients taking like opioid, is frequently prescribed and bought digoxin, clonidine, methyldopa, beta blockers, an- over the counter. It has been shown to cause neu- giotensin-converting enzyme (ACE) inhibitors, an- rological side effects, including hyperexcitability, giotensin-II blockers, calcium channel blockers increased muscle tone, and ataxia, other than sev- and diuretics. In particular, digitalis toxicity has eral neuropsychotoxic effects, such as maniac been shown to cause hallucinations, mania, eupho- episodes and dissociative symptoms, and poten- ria, and depression, in combination with visual tial abuse. Massive ingestions of the drug may be changes, gastroenteric (anorexia, emesis, abdomi- associated with untoward effects, including nal pain) and cardiovascular (arrhythmias) prob- tachycardia, hypertension, and respiratory de- lems. Thiazide diuretics, which minimally cross pression. Supra-therapeutic destromethorphan the blood-brain barrier, can result in neuropsychi- doses combined with a therapeutic amount of a atric complications, ranging from sedation to psy- SSRI may induce a serotonin syndrome69. chosis, due to their effects on electrolytes (primar- ily sodium and calcium). Some antiarrhythmic Gastroenterologic Drugs drugs have been associated with delirium in single Although prokinetic cholinergic agent meto- case reports. Amiodarone is associated with thy- clopramide is well-known for its side effects re- roid abnormalities in 15% of patients, and untreat- lated to dopamine blockade, its action at sero- ed thyroid dysregulation can lead to a variety of tonin receptors may also be clinically significant mood, cognitive, and psychotic symptoms. In con- in the genesis of neuropsychiatric side effects, trast, direct neuropsychiatric effects of amiodarone especially related to mood and behaviour. Anxi- are uncommon. Methyldopa, clonidine, and pro- ety, agitation, depression, suicidal but also homi- pranolol are associated with higher rates of fa- cidal ideation may follow brief exposure to meto- tigue, sedation and sleep disturbances than place- clopramide in occasional cases70,71. Anecdotal re- bo, related to their antiadrenergic actions50,64. Re- ports exist on psychosis accompanied by delu- cent interest has been focused on a potential risk sional beliefs, personality changes and disorien- of psychiatric adverse reactions associated with tation during Helicobacter pylori eradication statins. Special attention is currently being paid to treatment with amoxicillin, clarithromycin and the potential statin-induced sleep disorders (in- pantoprazole72. H2-histamine antagonists (cime- somnia, somnolence), the most other frequently tidine, ranitidine and famotidine) are known to reported psychiatric events being agitation, confu- cause secondary mania73. sion and hallucination65. Hormones Respiratory Drugs Neuropsychiatric and somatic side effects sig- The cumulative data indicate that psychiatric nificantly occur during treatment with supraphys- complications of corticosteroids are not rare, iological doses of thyroid hormones, comparable ranging from 6% (for severe reactions, including to hyperthyroid patients (see Part III). psychosis, other than mania and depression) to Discordant results are reported about the in- 23% for moderate reactions (anxiety and insom- creased odds ratios for depression in patients nia). Euphoria and hypomania were the most treated with progestogens. However, there is no common psychiatric symptoms reported during evidence of any association between lev- short courses of steroids, while during long-term onorgestrel and depression, despite of its in- treatment, depressive symptoms were the most creased occurrence among medroxyprogesterone common50,66. Hence, inhaled glucocorticoids and acetate users74. Depressive symptoms have been montelukast resulted the most frequently sus- reported during gonadotropin-releasing-hormone

79 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

(GnRH) agonists administration, but not conclu- of serotonin and inhibition of reuptake of nora- sive data exist. The association between the use drenaline. Its toxicity appears to be due to of oral contraceptives and depression is not monoamine uptake inhibition rather than its opi- clear. Depression is not considered a common oid effects79. Like tramadol, fentanyl, frequently side effect of hormone-based contraceptives, but used for analgesia during emergency procedures, negative mood symptoms remain one of the ma- is implicated in precipitating serotonin syndrome jor reasons for discontinuation of combined oral after intravenous administration, especially in pa- contraceptive pills75. tients chronically taking SSRIs80. Variable but significant percentage of patients Nonsteroidal anti-inflammatory drugs (NSAIDs), receiving finasteride seem to develop moderate another group of drugs extensively used in the to severe depression during the course of their treatment of pain, especially in the elderly, can treatment76. The adverse side of anabolic-andro- induce or exacerbate anxiety disorders, depres- genic steroids, synthetic drugs derived from sion, bipolar disorder and schizophrenia. These testosterone, included sexual dysfunction, alter- adverse effects may be more severe and frequent ations of the cardiovascular system, liver toxicity, than thought previously, but are generally transient psychiatric and behavioural disorders. Possibly and disappeared on withdrawal of the drugs81. The irreversible neuropsychiatric toxicity include de- anaesthetic agent ketamine, is also a potent anal- pendence syndrome, mood disorders, and pro- gesic and can be used in sub-anaesthetic doses to gression to other forms of substance abuse. Oc- relieve acute pain, especially in traumatic patient. casionally, anabolic-androgenic steroids abuse However, its psychotropic properties must be taken may be linked to certain social and psychological into account (see also before). traits of the user, like low self-esteem, low self- confidence, suffered hostility, childhood conduct Antibiotics, Antimalarials, disorder, and tendency to high-risk behaviour. Antituberculous and Antiviral Agents Use of anabolic-androgenic steroids in combina- Antibiotics are implicated in about 20% of all tion with alcohol largely increases the risk of vi- ED visits for drug-related adverse events, most olence and aggression. Both humans and animals visits being for allergic reactions. Since their in- exhibit a well-documented withdrawal syndrome, troduction in the 1930s, numerous (primarily mediated by neuroendocrine particularly opioi- anecdotal) reports described antibiotics induced dergic mechanisms, and cortical neurotransmitter psychiatric side effects, ranging from anxiety and systems77. panic to major depression, psychosis and deliri- um. Psychiatric toxicity may result from various Dermatologic Drugs mechanisms of action, including antagonism of First H1-histamine blockers (diphenhy- gamma-aminobutyric acid or pyridoxine, adverse dramine, promethazine), commonly having seda- interactions with alcohol, or inhibition of protein tive effect, can also induce stimulant effects on synthesis, sulfonamides and quinolones being CNS. Restlessness and insomnia may occur at mainly involved82. Ciprofloxacin, ofloxacin and usual therapeutic dosage. Convulsion may devel- pefloxacin are the quinolones with more neuro- op in children due to overdosage. Their anti- logical and psychiatric adverse reactions reported cholinergic and dopaminergic features may be re- in the literature. Dizziness, headache, tremors, lated to the development of delirium and acute insomnia, confusional state, mania, hallucina- psychosis70. Since the introduction of isotretinoin tions, and delirium being the most frequently re- (a retinoid receptor agonist) to the market, many ported psychiatric adverse events (0.9-11% of adverse psychiatric effects, including depression, patients). These events may affect not only sus- anxiety and suicide attempts were reported, with ceptible patients, such as elderly patients and in controversial results50,78. those using theophylline or NSAIDS, but also healthy patients83. Analgesics and Antinflammatory Drugs Reversible psychiatric illness was the most com- Potential adverse psychosocial effects, particu- mon comorbidity during macrolide antibiotic clar- larly for clinical depression and behavioural de- ithromycin, yet medication with neuroleptics or activation were detected among patients using benzodiazepine being required in the acute phase. chronic opioid therapy for chronic non-cancer Sometimes clarithromycin-induced delirium was pain. Tramadol is an analgesic medication with related to non-convulsive status epilepticus, so an partial mu agonist activity, also affecting release EEG is suggested to differentiate patients with psy-

80 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases chiatric illness from those with encephalopathy or ethionamide. Adverse reactions to cycloserine epilepsy84. Some authors suggest to add “antibio- and terizidone are mainly dose-related and espe- mania”, also called Hoigne’s syndrome, as part of cially occur when concomitantly administered the differential diagnosis when altered post-anaes- with other neurotoxic drugs, such as isoniazid thesia behaviour or psychiatric symptoms (delu- and ethionamide. Neurological (headache, verti- sions, paranoia, and hallucinations) are observed, go, dysarthria, somnolence, convulsion, mental especially when amoxicillin and clarithromycin are confusion, and memory deficit) and psychiatric administered85. Linezolid, a synthetic antibiotic adverse effects (psychotic states with catatonic, used to treat resistant gram-positive bacteria, can paranoid, and depressive reactions, with a risk inhibit MAO, so predisposing patients who are of suicide), are noted in up to 50% of patients90. concomitantly taking serotonin agonists to sero- Cycloserine is a second-line antituberculous tonin syndrome. Although cephalosporin are gen- agent, whose main side effects consist in CNS erally safe, neurotoxic effects have been reported manifestations, e.g. headache, irritability, de- in some subjects, with developing symptoms of pression, psychosis and convulsions. These psy- delirium during treatment86. chotropic responses are related to its action as a Metronidazole has good cellular penetration partial agonist of the neuronal NMDA receptor and is believed to penetrate the CNS easily. It can for glutamate. produce peripheral neuropathies and en- Neuropsychiatric adverse events, such as ab- cephalopathy with overall cerebellar dysfunction, normal behaviour, delusions, perceptual distur- similar to acute Wernicke encephalopathy, espe- bances, and delirium in children taking os- cially at dosages exceeding 2 g/day for prolonged eltamivir during the influenza season are report- periods. MR imaging shows characteristic lesion ed, although the available data seem do not sug- features and distributions. The mechanisms of gest a statistical significance91. Neuropsychiatric metronidazole neurotoxicity may differ for white side effects have been reported in individuals and gray matter lesions, presumably reflecting treated with efavirenz, commonly used in highly differences in degrees of edema, whether vaso- active antiretroviral combination therapy in the genic or cytotoxic in nature87. treatment of HIV infection. There are early com- The antimalarials chloroquine may achieve plications, such as acute psychosis resembling high concentrations in the brain having the same reactions to LSD intake, as well as generally dis- pathologic activity as the quinolones in acting as appearing nightmares, occurring for several days N-methyl-d-aspartate agonists and gamma- after the start of therapy. Late complications are aminobutyric acid antagonists, producing serious depressive episodes that must be carefully differ- psychiatric symptoms as a rare occurrence during entiated from pre-existing psychiatric disease and standard treatment, with symptoms of deperson- virus-induced brain damage92. alization and anxiety88. No severe but common and mainly neuropsychiatric adverse drug reac- Immunosoppressors and tions are described also during long-term anti- Immunomodulators malarial chemoprophylaxis with mefloquine. Cytokines such as IFN-alpha and interleukin-2 Anxiety, irritability, dizziness may frequently co- are often used in the treatment of certain cancers exists with digestive disorders anorexia, diar- (melanoma) and chronic diseases (hepatitis C in- rhoea and nausea89. fection and multiple sclerosis). Depression, anxi- The neuropsychiatric complications of antitu- ety, psychosis, suicidal ideation, hypomanic berculous agents are known for a long time, in- mood and cognitive impairment are reported in criminating usually isoniazid, which appears to patients who receive those medications. Dose-de- increase the concentrations of gamma-aminobu- pendent psychic disorders are noticed for about tyric acid in neural tissues. Aggressiveness, in- 30% of patients treated with IFN-alpha. Depres- somnia and memory problems may be noted, sion is the most frequently found psychiatric sometimes necessitating anxiolytics prescrip- pathology, its relatively high proportion in this tion. Hallucinations were also reported, espe- population (20-45%) raising important questions cially in patients having a history of alcoholism. about IFN tolerability/toxicity. Anxiety states are Peripheral neuritis, optic neuritis, diplopia, irri- not much described, and adaptation disorders are tability, anxiety, depression, hallucinations, con- more concerned with the announcement of the vulsions, and psychosis have been reported to diagnosis and its seriousness than with the toxici- occur in 1-2% of the patients treated with ty of the IFN-alpha molecule93.

81 A. Testa, R. Giannuzzi, F. Sollazzo, L. Petrongolo, L. Bernardini, S. Daini

Severe symptoms affect up to 5% of patients prescription drugs, whose psychostimulants (e.g., receiving the immunosuppressant cyclosporine amphetamines, methylphenidate) and modafinil and tacrolimus, and include psychoses and hallu- show significant effects on concentration, atten- cinations. Calcineurin inhibition by cyclosporine tiveness, and vigilance in healthy subjects99. and tacrolimus alters sympathetic outflow, which Modafinil is a waking drug commercialized in may play a role in the mediation of neurotoxic 2003 for sleep apnea and narcolepsy patients, but effects94. its use as a lifestyle drug is increasing, namely as a non-prescription medicine for students, hard- Antineoplastics working professionals, athletes and soldiers. Thus Chemotherapeutic drugs for cancer treatment modafinil may induce wakefulness by its action in are, of necessity, cytotoxic. Recently the term the anterior hypothalamus, by activating orexin “chemo-fog” was proposed to describe potential neurons. Orexin is a family of wakefulness-pro- deleterious adverse effects on cognitive function moting and sleep-inhibiting peptides, involved in due to excessive cytokine release by the cytotoxic inducing narcolepsy. The disruption of circadian agents95. The so-called “chemobrain” is a complex rhythm and sleep control may influence the neuro- phenomenon, and various factors other than immune circuits, inducing stress responses and chemotherapy may affect cognitive function, in- impairing immune functions. Modafinil increases cluding the impact of surgery and anaesthesia, resting heart rate and blood pressure, inducing hormonal therapy, menopause, supportive care sympathomedullary activation47. GHB has also medications, genetic predisposition, comorbid achieved popularity as a recreational drug and a medical conditions, or possibly paraneoplastic nutritional supplement marketed to bodybuilders37. phenomenon96. CNS toxicity of chemotherapeutic The problem of anabolic-androgenic steroid abuse drugs can manifest in many ways, including en- has recently generated widespread public and me- cephalopathy syndromes and confusional states, dia attention (see Hormones section). Different alterations in cognition and consciousness, cere- classes of doping substances, namely stimulants, bellar dysfunction, seizures, headache, cerebrovas- narcotics, cannabinoids, beta2-agonists, diuretics, cular complications and stroke, visual loss, spinal glucocorticosteroids, beta-blockers and others, cord damage and psychiatric symptoms including may cause psychiatric adverse reactions and a dissociative symptoms and psychosis. For many wide range of cardiac arrhythmias (focal or re-en- drugs, the toxicity is related to route of administra- try type, supraventricular and/or ventricular), tion and cumulative dose, and can vary from brief, through a direct or indirect arrhythmogenic effect, transient episodes to more severe, chronic seque- that can even be lethal and which are frequently lae. However, the neurotoxicity can be idiosyn- sport activity related100. cratic and unpredictable in some cases. The most common chemotherapeutic agents that might cause CNS toxicity manifested as encephalopathy References of various severities include methotrexate, vin- cristine, ifosfamide, cyclosporine, fludarabine, cy- 1) PALIJAN TZ,MUZINI L,RADELJAK S. Psychiatric co- tarabine, 5-fluorouracil, cisplatin and L-asparagi- morbidity in forensic psychiatry. Psychiatr Danub nase97. Studies indicate that also doxorubicin and 2009; 21: 429-436. cyclophosphamide are significantly associated 2) NARROW WE, KUHL EA. Dimensional approaches to with psychiatric disorders, including generalized psychiatric diagnosis in DSM-5. J Ment Health Policy Econ 2011; 14: 197-200. anxiety disorder, panic disorder, PTSD, adjust- 3) SARAVANE D, FEVE B, FRANCES Y, CORRUBLE E, LANCON ment disorders, major depressive disorder and C, CHANSON P, MAISON P, TERRA JL, AZORIN JM. Draw- dysthymic disorder, in patients with first breast ing up guidelines for the attendance of physical cancer recurrence98. There have been occasional health of patients with severe mental illness. En- instances of CNS toxicity after paclitaxel treat- cephale 2009; 35: 330-339. ment though the syndrome is not well described. 4) KAPFHAMMER HP. The relationship between depres- sion, anxiety and heart disease–a psychosomatic challenge. Psychiatr Danub 2011; 23: 412-424. Doping Agents 5) DURAZZO M, SPANDRE M, BELCI P, PASCHETTA E, PREMOLI Athletes use substances to produce pleasure, re- A, BO S. Issues of internal medicine in psychiatric lieve pain and stress, improve socialization, recov- patients. Minerva Med 2010; 101: 329-352. er from injury, and enhance performance. “Brain 6) REGIER DA, FARMER ME, RAE DS, LOCKE BZ, KEITH SJ, doping” refers to the illicit use of a subcategory of JUD LL, GOODWIN FG. Comorbidity of mental disor-

82 Psychiatric emergencies (part II): psychiatric disorders coexisting with organic diseases

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