Introduction to Criminology: Understanding Crime and Its Societal Impact
Delve into the interdisciplinary field of criminology, exploring crime as a social phenomenon, its causes and effects on individuals and society. Learn about the origins of criminology, its relationship with other penal sciences, and the various fields within this complex discipline. Discover key concepts such as victimology, criminal etiology, phenomenology, and more. Dive into historical studies in criminology, including the anthropological direction and early research on crime as a scientific phenomenon.
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Quotes from Principles and Practices of Psychopharmacotherapy by Philip Janicak Study Guide updated July 02, 2018
Note This deck consists completely of quotations from Principles and Practice of Psychopharmacotherapy (4thed) by Philipp G. Janicak, et al. It is designed to be a study guide and address some of the issues that have proven to be most challenging to students at SAH. It is incomplete, for example, in that it mainly addresses antipsychotics and antidepressants. Mood stabilizers would require another twenty slides, etc., not included. It is a good faith, best effort to help the students study. All the usual disclaimers apply. 2
Case 1 A 37-year-old schizoaffective patient was treated with thioridazine (100 mg by mouth 4 times daily), phenytoin (100 mg by mouth 4 times daily), and amitriptyline (50 mg by mouth 4 times daily). The patient had been stabilized on this regimen for several weeks, but then complained of daytime sedation. The treating physician therefore combined all three into a single bedtime regimen. The patient expired the first night of the new schedule from an acute cardiac arrest. In this case, each of the drugs the patient was taking was individually capable of slowing intracardiac conduction in a concentration-dependent manner. Death occurred as a result of their additive effect amplified by the decision to combine all three in a single nighttime dose. That decision substantially increased the peak concentration of each drug and consequently resulted in a fatal arrhythmia. 3
Pharmacokinetics The principal route of administration for psychoactive drugs is oral, with absorption generally occurring in the small bowel. The drug is then absorbed into the portal circulation and enters the liver. Drugs can be metabolized by cytochrome P450 (CYP) enzymes in both the bowel wall and in the liver before reaching the systemic circulation (i.e., first-pass metabolism). Most psychiatric medications are highly lipophilic, so they readily pass the blood - brain barrier and enter the central nervous system (CNS). In addition, because of their high lipophilicity, they generally share several other features: Rapid and complete absorption Rapid and extensive distribution in tissue compartments High first-pass effect Large volume of distribution 4
Pharmacokinetics Drug concentration determines which site(s) of action a drug will engage and to what degree. Concentration is determined by a drug's pharmacokinetics, or what the body does to the drug. Pharmacokinetics literally refers to drug movement, which is divided into four phases: Absorption of the drug from the site of administration Distribution through the body Metabolism or biotransformation into more polar metabolites Elimination from the body 5
Alcohol has a triphasic effect on the elimination rates of drugs that require extensive biotransformation . For example, acute alcohol ingestion can significantly block the metabolism of high first-pass clearance drugs (e.g., TCAs). This chemical inhibition can substantially increase the bioavailability of such drugs and their effects, such as the increased lethality of a TCA overdose when taken together with alcohol. 6
Cytochrome P450 Enzyme Induction Drinking alcohol on a regular basis for several weeks to months can induce CYP isoenzymes such as CYP 1A2 and 3A3/4, resulting in a lower plasma concentration of drugs dependent on (p. 28) these enzymes for their clearance (e.g., olanzapine, which is principally a CYP 1A2 substrate, or quetiapine, which is principally a CYP 3A3/4 substrate). Thus, subacute and subchronic alcohol consumption induces liver enzymes and causes lower plasma levels of drugs that undergo oxidative biotransformation as a necessary step in their elimination. 7
Cytochrome P450 Enzyme Induction In contrast to anticonvulsants and alcohol, drugs such as fluoxetine, paroxetine, fluvoxamine, bupropion, nefazodone, quinidine, and some antipsychotics can inhibit specific CYP isoenzymes . Thus, drugs whose metabolism is dependent on these enzymes (e.g., many of the antipsychotics, antidepressants, and anxiolytics discussed later) can have their clearance reduced by the co-administration of agents such as fluoxetine. For example, fluoxetine at 20 mg per day produces on average a 500% increase in the levels of coprescribed drugs that are principally dependent on CYP 2D6 for their clearance. That can lead to an increased incidence and severity of dose- and concentration-dependent adverse effects. Such a situation may even be life threatening if the drug has a narrow therapeutic index and the dose is not adjusted for the change in its clearance. 8
Case Example A 44-year-old chronic alcoholic man presented in the emergency room with disorientation and combativeness after 2 days of abstinence. He complained of visual and tactile hallucinations and was found to have elevated heart rate, blood pressure, and temperature. Lorazepam was slowly administered intravenously, and after 15 minutes, the patient was mildly sedated. He was then transferred to an inpatient unit. During this 30-minute interval, he received no additional lorazepam, and when he arrived on the floor, his symptoms had returned. He became agitated, struck one of the nursing staff, and had to be physically restrained. In this case, failure to account for the phenomenon of drug redistribution resulted in a potentially avoidable adverse outcome. 9
Case Example A 62-year-old man presented to his internist with a major depressive disorder. His past medical history was significant for two previous myocardial infarctions and related congestive heart failure, well controlled by digoxin. There was also a past history of significant alcohol abuse, in remission for the past 4 years. The internist prescribed amitriptyline (75 mg by mouth at bedtime). One week later, the patient returned with a worsening of his depressive state, and the internist increased the dose to 100 mg. The patient continued to deteriorate and was referred to a psychiatrist, who hospitalized him. The patient was now suspicious, guarded, and irritable and was given the diagnosis of a psychotic depression. Haloperidol (10 mg by mouth at bedtime) was added. Five days later, the patient was found unconscious in his room after complaining of faintness and heart palpitations. He was rushed to the coronary intensive care unit, where a 2:1 atrioventricular block and periodic runs of premature ventricular contractions were found on the electrocardiogram (ECG). Drug level monitoring revealed a total TCA plasma level of 950 ng/mL. All psychoactive drugs were stopped. As the plasma level fell, the cardiac and the psychotic symptoms resolved. This patient had several risk factors for the development of toxic TCA concentrations even while on a relatively low dose of amitriptyline. 10
Case Example Case Example A 48-year-old bipolar woman, stabilized on lithium 1,200 mg per day for the past 6 months, had a plasma level that varied between 0.8 and 1.0 mEq/L. She developed a recurrence of her rheumatoid arthritis, for which her internist prescribed ibuprofen (800 mg 3 times daily). A week later she was brought to the emergency room in a confused, disoriented, and lethargic state. She was also ataxic and had periodic generalized myoclonic jerks. TDM revealed a lithium level of 4.0 mEq/L, and despite a rapid fall to under 0.5 mEq/L with plasma dialysis, her neurological status continued to deteriorate. After 5 days she died. Failure to account for a critical drug interaction affecting the renal clearance of lithium resulted in an otherwise avoidable fatality. 11
Alterations in Pharmacokinetics As an example, certain anticonvulsants (e.g., CBZ, phenobarbital) potently induce specific CYP isoenzymes (principally CYP1A2 and 3A), causing plasma levels of antipsychotics to fall because of an acceleration in their metabolism. Thus, the addition of CBZ to control mood swings in a psychotic patient previously stabilized may precipitate a psychotic exacerbation or relapse unless the antipsychotic dose is adjusted to compensate. Conversely, other psychotropics (e.g., SSRIs) can inhibit specific CYP isoenzymes, increasing the levels and the potential toxicity of concomitantly prescribed drugs dependent on that isoenzyme for their clearance 12
Alterations in Pharmacokinetics For example, fluoxetine and paroxetine substantially inhibit CYP 2D6, important in the oxidative metabolism of drugs such as the TCAs. This effect can result in a quadrupling of the plasma concentration of TCAs and other CYP 2D6 substrates/drugs, potentially causing serious toxicity unless the dose is reduced. [P. 32] 13
Applications of Pharmacokinetics For example, lorazepam is rapidly absorbed from the gastrointestinal tract into the systemic circulation and from there distributed into the brain. In contrast, oxazepam, the most polar BZD, is slowly absorbed from the gastrointestinal tract. Even after oxazepam moves into the systemic circulation, it enters tissue compartments, including the brain, slowly during the distribution phase. 14
Applications of Pharmacokinetics Unlike lorazepam, oxazepam is not available in either the intramuscular or intravenous formulations. Thus, lorazepam would be preferable to achieve acute control of alcohol withdrawal (e.g., delirium tremens), whereas oxazepam would better stabilize a dependency-prone patient on sedative - hypnotics because it does not cause the euphoria seen with the more rapidly absorbed members of this class. 15
Applications of Pharmacokinetics Longer-acting BZDs (e.g., clonazepam) have their own built-in taper due to slow clearance, allowing time for readjustment of compensatory changes in the brain that eliminate or blunt withdrawal symptoms. In contrast, BZDs P.33 with very short half-lives (e.g., alprazolam) are more likely to produce withdrawal syndromes . This is the rationale for switching short-half-life BZD-dependent patients to an equipotent dose of a long-lived BZD, which can then be tapered more safely. The same is true for the withdrawal syndrome that can occur with SSRIs, being more common with short- (e.g., fluvoxamine, paroxetine) than with long-half-life (e.g., fluoxetine) members of this class. 16
Antipsychotics The therapeutic efficacy of clozapine, the first truly different antipsychotic, has spawned the development of a succession of newer agents [e.g., risperidone (RISP), olanzapine (OLZ), quetiapine (QTP), ziprasidone (ZPD), and aripiprazole (ARIP)]. Other new compounds (e.g., bifeprunox, paliperidone, asenapine) may also receive U.S. Food and Drug Administration (FDA) marketing P.82 approval in the near future. 17
Antipsychotics This text refers to these drugs as first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). FGAs include all of the agents marketed before clozapine. Currently marketed SGAs worldwide include clozapine, sulpiride, amisulpride, zotepine, RISP, OLZ, QTP, ZPD, and ARIP. Although these agents have previously been referred to as atypical or novel, these terms now seem dated as SGAs have become the most commonly prescribed antipsychotic agents in the United States, Canada, and most other countries. 18
Extrapyramidal reactions, particularly parkinsonian symptoms, can be a major adverse effect of many of these drugs, as well as an important clue to their mechanism of action. True Parkinson's disease is caused by a DA deficiency in the nigrostriatal system. 19
Clonzapine Postmortem studies of patients with idiopathic Parkinson's disease demonstrate cell loss in the striatal system (A-9), directly implicating this tract vis- -vis the drug-induced pseudoparkinsonian adverse effects. The assumption that psychosis is related to the A-10 system is made by exclusion. Evidence also indicates that clozapine may differentially block DA pathways. Specifically, it seems to act on the mesolimbic dopaminergic system (A-10), while being relatively inactive in the striatal system (A-9); however, this remains controversial. Chronic administration of clozapine decreases the firing rate of A-10 mesocortical tract dopamine neurons while sparing A-9 neurons of the nigro-striatal pathway. By contrast, FGAs reduce the firing rate of both A-9 and A-10 neurons. 20
Increasing Dopaminergic Activity If decreasing dopaminergic activity benefits psychosis, what is the effect of increasing dopaminergic activity? Potentiation of DA by a variety of mechanisms is a common denominator for inducing paranoia, hallucinations, and other manifestations of psychosis. For example: 21
Increasing Dopaminergic Activity L-Dopa (3,4-dihydroxyphenylalanine), which is converted to DA in the body, can produce psychosis as a side effect Amantadine, another dopaminergic drug, can also induce psychotic symptoms Stimulants, such as amphetamine and methylphenidate, are potent releasers of DA, whereas cocaine also interferes with its reuptake, increasing DA concentrations at synaptic sites; all can produce paranoid reactions in some abusers Bromocriptine, apomorphine, lisuride, and other direct-acting DA agonists benefit Parkinson's disease and can also cause psychotic reactions at high doses 22
Increasing Dopaminergic Activity As noted, large doses of amphetamine, cocaine, and other sympathomimetics can cause acute paranoid reactions, either spontaneously in abusers or experimentally in normal volunteers. An injection of a large amphetamine dose in normal control subjects, for example, often produces a paranoid psychosis resembling schizophrenia within hours. Frequent smaller doses over several days can also produce a paranoid psychotic reaction. The duration of an episode usually parallels the length of time the drug remains in the body. 23
Dopaminergic Activity Interestingly, when physostigmine, a drug that increases brain acetylcholine (ACh), is administered before methylphenidate, it prevents the exacerbation, indicating that the worsening may be mediated by a dopaminergic - cholinergic imbalance . Physostigmine itself, however, does not reduce psychosis, suggesting that the underlying process is not amenable simply to altering cholinergic tone. Subsequently, nicotinic cholinergic receptors have been reported to play an important role in the inhibition of the perception of extraneous environmental stimuli. This observation has implications for the deficits in sensory gating reported in schizophrenia. 24
Dopaminergic Activity One leading hypothesis as to why newer agents produce fewer EPS and perhaps provide P.8 greater benefit for negative symptoms is that they have a more potent effect on the serotonin 5-HT2receptor subtype. Thus, the ratio of 5-HT2 to D2blockade has become an important measure of the potential atypicality" of an agent. In addition, these novel antipsychotics have a neuroreceptor profile that differs substantially from that of the FGAs. 25
Antipsychotics For example, clozapine is a dibenzothiazepine derivative with affinity for a variety of neurotransmitter receptors, including several serotonin receptors (5-HT1C 5-HT3, 5-HT6, and 5-HT7) that may modulate dopamine activity and contribute to the atypical action of this agent. It is likely that clinically effective doses of clozapine also antagonize 5- HT2A and 5-HT2C receptors. The resulting increased 5- HT2A/D2 ratio may be one basis for the unique antipsychotic efficacy of clozapine. At clinical doses, clozapine also has a lower affinity for D2 receptors, which may account for its decreased propensity to evoke EPS, as well as its negligible neuroendocrine effects. Other agents (e.g., ZPD, ARIP) are partial agonists at the 5-HT1A receptor, which may also modulate DA activity. 26
Evidence from a number of sources suggests that clozapine reduces the risk of suicide in schizophrenia. The most obvious source emerged from the treatment of patients who had previously been severely psychotic and unresponsive. Improvement in these individuals appeared to be associated with a decreased risk of suicide . Other studies found that patients with schizophrenia who were treated with clozapine had much lower rates of completed suicide than other populations with schizophrenia 27
Evidence from a number of sources suggests that clozapine reduces the risk of suicide in schizophrenia. For example, Reid et al. found that the annual rate of completed suicide among patients with schizophrenia treated by the Department of Mental Health in Texas was 63.1 per 100,000. In contrast, from an apparently similar group of patients who received clozapine, there was only one completed suicide (i.e., 12.7 per 100,000). The authors noted that this rate was similar to the rate in a clozapine national registry. 28
Starting Clozapine Starting doses for clozapine should be in the range of 12.5 to 50 mg per day and titrated up slowly to minimize hypotension. There is evidence that some patients develop hypotension or apnea when started on as little as 25 mg. This has led to the suggestion that patients be started on as little as 12.5 mg. The usual therapeutic range is 300 to 500 mg per day (the recommended maximum dose is 900 mg/day). As hypotension or seizures may occur with a more rapid early titration, we recommend increasing the dose by only 25 to 50 mg every 3 to 7 days depending on the patient's tolerance. 29
Quetiapine Early PET studies of QTP receptor occupancy indicated substantially lower D2 occupancy than with other SGAs, with the exception of clozapine, which is also associated with lower occupancy This suggests that transient occupancy may be sufficient for an antipsychotic effect. These observations provide strong support for Seeman's proposal that an important property of SGAs is their ability to occupy D2 receptors briefly and then rapidly dissociate from them to allow normal dopamine neurotransmission. 30
Starting Clozapine In this context, Perry et al. found a therapeutic threshold clozapine plasma level of 350 ng/mL (i.e., 64% with levels above this responded, versus only 22% with levels below this point), which required an average dose of 380 mg per day. The usual therapeutic dose is typically achieved in 3 to 6 weeks. As hypotension or seizures may occur with a more rapid early titration, we recommend increasing the dose by only 25 to 50 mg every 3 to 7 days depending on the patient's tolerance. 31
Aripiprazole Aripiprazole (ARIP) is the first approved antipsychotic that is not a pure D2antagonist. Rather, it is a partial agonist at D2 (as well as 5-HT1A) receptors. Like other SGAs, it is also an antagonist at the 5-HT2 receptor. As an effective partial agonist (5), ARIP binds with high affinity to D2 receptors but with a lower level of intrinsic activity. As a result, if there are high levels of dopamine in a particular area of the brain, ARIP will replace dopamine, leading to a reduced dopamine effect due to its lower intrinsic activity. If an area is low in dopamine, ARIP can lead to a net increase in dopamine activity 32
Aripiprazole Aripiprazole (ARIP) is the first approved antipsychotic that is not a pure D2antagonist. Rather, it is a partial agonist at D2 (as well as 5-HT1A) receptors. These differing actions at DA receptor subtypes in distinct cellular locations may produce different functional results in comparison with drugs that are D2 postsynaptic receptor antagonists only. Theoretically, this could lead to improving psychosis by decreasing dopamine activity in limbic areas and possibly improving negative symptoms and cognitive impairments by indirectly (e.g., via 5-HT effects) increasing dopamine activity in frontal areas. 33
Benzodiazepines BZDs may be given to patients with moderate agitation. These agents also are the treatment of choice in alcohol withdrawal states characterized by agitation, tremors, or change in vital signs 34
Lorazepam Lorazepam has been extensively studied for control of psychotic aggressivity. One reason is that, of all the BZDs available in parenteral form, lorazepam has a pharmacokinetic profile (quick, reliable absorption) that makes it particularly suitable for this type of use. Open, retrospective, and controlled studies indicate that oral or parenteral lorazepam added to an antipsychotic controls disruptive behavior safely and effectively for most patients. The combination may also permit an overall reduction of the antipsychotic dose, although this assumption requires further study. 35
Catatonia. Catatonia is a syndrome that can present as a symptom of several disorders. A large number of case reports have found that BZDs are effective in the treatment of catatonia. Specifically, lorazepam, clonazepam, and diazepam have been reported to induce temporary remission of catatonic symptoms. BZD treatment of catatonia is usually considered diagnostic, however, because symptoms return as the therapeutic effect of the drug wanes. 36
Antidepressants plus antipsychotics Preliminary findings indicate that the addition of fluoxetine may increase response or benefit treatment- resistant schizophrenia patients. Further, deficit symptoms seemed to improve in some patients, supporting a possible role for 5-HT2 hypersensitivity as the underlying mechanism . Care must be taken to monitor plasma levels of antipsychotics, which may rise when combined with this selective serotonin reuptake inhibitor (SSRI) or other related antidepressants due to their ability to inhibit various CYP isoenzymes. 37
Adverse Effects of Antipsychotics The effectiveness of any pharmacological treatment in medicine should be balanced against its unwanted effects. For the antipsychotics, these effects can vary from those that are mildly discomforting to those that can seriously affect an individual's health. The long list of adverse effects for antipsychotics may suggest that most patients experience many of these effects to a significant degree 38
Adverse Effects of Antipsychotics In fact, although almost all patients will experience some mild effects with these drugs, such as dry mouth or tremor, they are usually transitory and disappear with time, medication reduction, or discontinuation. Fortunately, these effects are rarely serious or irreversible, and on average the typical complications with antipsychotics are no worse than those with medications prescribed for other medical disorders. 39
Central Nervous System Acute Extrapyramidal Side Effects Acute EPS can be classified into three categories: Parkinsonian syndrome Acute dystonias Akathisia Lower-potency FGAs, such as thioridazine and CPZ [clorpromazine], have a decreased incidence of EPS when compared with higher-potency agents, such as HPDL or fluphenazine. SGAs, such as clozapine and QTP, are nearly devoid of EPS when given within their recommended dosing range. 40
Central Nervous System Acute Extrapyramidal Side Effects The parkinsonian syndrome is characterized by a masklike facies, resting tremor, cogwheel rigidity, shuffling gait, and psychomotor retardation. A more subtle form may present as emotional blunting (e.g., an apathetic appearance lacking in spontaneity) and a relative inability to engage in social activities, which can be confused with the emotional withdrawal, apathy, and retardation that are part of the deficit syndrome associated with a schizophrenic disorder or a postpsychotic depression. 41
Central Nervous System Acute Extrapyramidal Side Effects The syndrome is symptomatically identical to idiopathic parkinsonism and responds to antiparkinsonian medications (e.g., benztropine). Parkinsonian rigidity and akinesia may also respond to amantadine. Rarely, antipsychotics have been reported to produce a catatoniclike state, similar to akinetic mutism, which may also be responsive to amantadine. 42
Central Nervous System Acute Extrapyramidal Side Effects The dystonias are involuntary contractions of major muscle groups and are characterized by symptoms such as torticollis, retrocollis, oculogyric crisis, and opisthotonos. P.142 Akathisia is a motor restlessness manifested by the urge to move about and/or an inability to sit still. This can be confused with psychotic agitation because patients are driven by a restlessness that is primarily motor in origin and that cannot be controlled by their own volition 43
Central Nervous System Acute Extrapyramidal Side Effects P.142 Akathisia: . In addition, patients with milder akathisia may experience a subjective feeling of restlessness but not demonstrate abnormal motor behavior. Unlike psychotic agitation, however, akathisia is accompanied by subjective distress, worsened by increasing the antipsychotic dose, and often benefited by a decrease in antipsychotic dose or the addition of a beta-blocker or a BZD. 44
Central Nervous System Acute Extrapyramidal Side Effects The parkinsonian syndrome and akathisia often occur early in therapy and tend to persist if not treated. They can also appear years later after prolonged treatment, often coexisting with TD. EPS, in general, occur equally in both sexes and in all ages; however, there are age- and sex-related differences in the incidence of various types of EPS. 45
Central Nervous System Acute Extrapyramidal Side Effects Although these adverse effects have fairly characteristic presentations, their diagnosis can occasionally be missed. For example: Dystonia can be confused with bizarre mannerisms Akathisia can be confused with agitation Parkinsonian akinesia can be confused with negative symptoms such as schizophrenic apathy or a retarded depression 46
Late-Onset (Tardive) Extrapyramidal Side Effects TD presents with abnormal involuntary movements, usually associated with chronic (i.e., longer than 2 years) antipsychotic therapy. Although there is some debate whether the antipsychotics are either necessary or sufficient to produce this syndrome in psychiatric patients, the consensus is that they at least play an important role. TD is characterized by: P.144 47
Late-Onset (Tardive) Extrapyramidal Side Effects P.144 Buccolinguomasticatory movements: Sucking, smacking of lips Choreoathetoid movements of the tongue Lateral jaw movements Choreiform or athetoid movements of the extremities and/or truncal areas Any combination of these symptoms 48
Masked Depression It is important to recognize that a depressed mood is not synonymous with a depressive episode. Conversely, an episode of depression may not present with a mood complaint, but rather with associated symptoms such as insomnia or other somatic complaints. This is particularly true for the elderly and for those seen in primary care settings 49
Masked Depression It is important to recognize that a depressed mood is not synonymous with a depressive episode. Even when a mood complaint is prominent, it may not be described as depressed, but instead as irritable or anxious. Thus, patients with MDD may have a variety of complaints other than depressed mood, such as insomnia, fatigue, or somatic symptoms. Failure to recognize that MDD underlies such complaints can lead to unnecessary and costly tests, as well as a delay in effective treatment. Complaints may also vary by age group 50
