By I. Killian. Wake Forest University.
Nonbiological events are clearly symptoms in children present distinctive diagnostic and more influential because purchase 50 mg indocin free shipping arthritis in lower back sciatica, in most respects discount indocin 75mg mastercard rheumatoid arthritis diet gluten free, children are more clinical challenges because of the powerful influences of im- vulnerable to their surroundings purchase 75 mg indocin with mastercard arthritis medication with coumadin. Immaturity makes chil- maturity and the moving target produced by development order indocin 75 mg line arthritis in your neck and back. Children routinely have intrusions of fan- about whether children are capable of having psychotic tasy into ordinary mental life; determining when this becomes pathologic can be a matter of degree. Children learn and experiment with imitation, and they can acquire habits and strategies used by those around them. Towbin: Complex Developmental Disorders Clinic, De- ner. When one examines a 5-year old child who claims hood psychoses. Nevertheless, there came an acknowledg- that he is 'superman and can fly,' the challenge is to deter- ment and new awareness of major developmental differences mine whether the child has a delusion. Similarly, in a child in the perception of reality (12) and that developmentally who complains about hearing a voice telling her to 'do bad or culturally appropriate beliefs (e. This cluster of syndromes, including infantile au- This must be distinguished from make-believe (e. Children can describe this make- of language, perception, and motility (11). Although psy- believe phenomenon, and clinicians need to discern the dif- chotic speech and thoughts were initially considered inher- ferences as they work with children with symptoms of psy- ent components of childhood schizophrenia, hallucinations chosis. Such characteristics are sought by the clinician in and delusions were not required criteria (6,13–15). The task and adopted this nosology and grouped all childhood psychoses challenge as child and adolescent psychiatrists are to ask the under childhood schizophrenia. As a result of this broad right questions, to differentiate delusions and hallucinations grouping, the literature regarding childhood schizophrenia from other forms of thought, such as a vivid imagination from this period overlaps with that of autism and does not in a young child. With further development of psychiatric taxonomy and elucida- tion of the phenomenology (course, onset, family history, HISTORY and associated features), the distinctiveness of the various childhood psychoses and the similarity between child and Interest in childhood psychosis can be traced to the nine- adult schizophrenia were demonstrated (16,17). This teenth century, when Maudsley first wrote a description of change had a pronounced influence on the nosology of these the 'insanity of early life' in 1874 in his textbook, Physiology disorders and led eventually to changes with the DSM-III and Pathology of Mind (4). Schizophrenia arising in childhood and infantile au- proach by noting that the mental faculty of children was tism came to be recognized as distinct clinical syndromes, not organized, and hence the insanity in children must be each with its unique and distinct psychopathologic phe- of the simplest kind, influenced more by 'reason of bad nomenology, theories about causes, and longitudinal course. This distinction has had an impact on hood schizophrenia as different from mental deficiency and how children with these disorders are currently evaluated, from certain neurologic disorders, such as epilepsy or postin- managed, and treated. It was not until 1919, that Kraeplin introduced the concept of dementia praecox and noted its onset in late childhood and adolescence (6). Given COGNITIVE ASPECTS the insidious onset of the disorder, Kraeplin cautiously sug- gested that 3. This led to less may complain of changes in their mental and cognitive an increased interest in understanding the developmental states. To these changes, clinicians add signs, based on ob- aspects of psychosis. Historically, despite this early descrip- servations derived from the mental state examination of the tion of the syndrome by Kraeplin that is now recognized children and data obtained from laboratory or cognitive as schizophrenia, other diagnostic terms were put forward as tests. Subsequently, a distinctive pattern may emerge over well. Psychotic symptoms age, and offered specific diagnostic criteria for children (8). Cognitive impairments, particularly im- nia and autism. From a cognitive and developmental standpoint, certain It is critical to avoid rushing to a premature conclusion clinical features in children create diagnostic challenges. Such atypi- One problem is distinguishing true psychotic phenomena cal mental experiences in children can be recognized as pro- in children from nonpsychotic idiosyncratic thinking, per- dromal or prepsychotic signs only after the manifestation ceptions caused by developmental delays, exposure to dis- of frank psychotic symptoms. Odd beliefs and unusual be- turbing and traumatic events, and overactive and vivid haviors deserve close observation, but they cannot be as- imaginations. Furthermore, because the onset of childhood cribed to psychosis without the concomitant presence of a schizophrenia is insidious, with a lifelong history of develop- thought disorder. It has also been suggested that the develop- when her disorder had its onset, she noted that the sound ment of psychotic conditions during childhood may have of the train whistle changed, and she began to wonder why. Until that time, such events Investigators have noted that social withdrawal, 'shy- were inconsequential and unimportant, but at about age 11 ness,' and disturbances in adaptive social behavior seem to years, she started to attach a different meaning to them. She be the first signs of dysfunctional premorbid development. Things around her nerability factors, indicative of a risk of psychotic illness started to have special meaning, her thoughts were (22). Recent work has also pointed to early language deficits 'strange,' and she was puzzled and bewildered. Over the next several years, she However, a socially odd child is not usually schizophrenic. She believed that the train whistle was schizophrenic (24–26), because they lack the requisite per- sending special messages from God to her. Intellectual delays have questioned these perceptions and believed them to be real. Distinguishing between the formal thought disorder of schizophrenia and that of developmental disorders, person- ality disorders, and speech and language disorders also pre- sents diagnostic problems (30). Symptoms such as thought CLINICAL AND DEVELOPMENTAL disorder have been noted to arise in persons with pervasive CONSIDERATIONS developmental disorders, particularly those with good lan- guage skills, such as (often referred to as 'high functioning') Developmental factors influence the detection, form, and autistic persons and those with Asperger syndrome (31,32). One problem Although loose associations and incoherence are valid of assessing psychotic disorders in very young children com- diagnostic signs of early-onset schizophrenia, these symp- pared with older children is that these symptoms in young toms are also sometimes seen in schizotypal children (33). Isolated The inclusion criteria of disorganized speech according to hallucinations can occur in acutely anxious but otherwise DSM-IV (34), rather than a formal thought disorder, pre- developmentally intact preschool children. In older chil- sents a particular challenge when assessing children, because dren, hallucinations may occur in the absence of other signs disorganized speech is an inherent component of many of of psychosis, but they are usually associated with other psy- the developmental disorders. Clearly, the assessment and chopathologic conditions, such as depression, severe anxi- ascertainment of delusions, hallucinations, and thought dis- ety, and posttraumatic stress disorder. Further, it in the differential diagnosis of a child presenting with psy- is often too difficult to tease out the physiognomic-animistic chotic symptoms. The use of comparable criteria across the interpretations of the inner and outer world on one hand age span facilitates analyses of progressive symptoms from 616 Neuropsychopharmacology: The Fifth Generation of Progress childhood to adulthood. However, one of the difficulties otherwise specified, the NIMH group preferred to consider in assessing psychotic disorders in very young children is the constellation a forme fruste of schizophrenia (46). Yet to determine whether nonspecific behavioral disturbances longitudinal studies suggested that the constellation remains represent an incipient psychosis or are signs of autism or stable and does not progress to schizophrenia (46). As further explora- tention, especially as it relates to childhood-onset schizo- tion now points to 'high rates of speech and language, phrenia (37). Therefore, another alternative in the concep- motor, and social impairments in patients with childhood- tualization of psychotic episodes is a grouping of symptoms onset schizophrenia,' the association with pervasive devel- that are not part of the formal DSM or International Classi- opmental spectrum disorders is drawn even closer for this fication of Diseases (ICD) scheme. For decades, clinicians very early-onset subgroup (23). Early references on schizophrenia (17) and later writ- hood psychoses can be classified as described in the follow- ings (38,39) noted the diagnostic problem of children with ing sections. Now, the absence of a formal single diagnostic address for this syndrome has produced a wide variety of terms applied to the same phe- Functional Psychoses nomena. The older literature suggested that such children Childhood-Onset Schizophrenia may be considered to have 'borderline syndrome of child- hood' (40), and then later 'schizotypal disorder of child- Schizophrenic psychoses with onset before age 11 years are hood' was considered (38). In addition, developmental status can affect the this condition was best understood as a developmental de- expression of the disorder. The earliest descriptions by De- viation within the group of pervasive developmental disor- Sanctis (5), Bleuler (49), and Kraeplin (6) reported the onset ders (41).
The indications for ECT anticonvulsant hypothesis unifies many of the scientific were established during this time indocin 25mg cheap arthritis medication starting with p, and its use in conditions findings in electroencephalography purchase 50mg indocin with mastercard getting arthritis in fingers, neuroimaging order indocin 25mg with visa additive arthritis definition, and other than mood disorders and schizophrenia diminished trusted 75 mg indocin arthritis in back at 30 years old. This hypothesis as- depression and was one of the most significant medical ad sumes that ECT enhances the transmission of inhibitory vances in the twentieth century. However, in 1950 the mor neurotransmitters and neuropeptides and that the active tality and morbidity from ECT were unacceptably high and process of inhibiting the seizure is essential to the therapeu- most of the early research in ECT focused on the safety and tic action of ECT. New data are presented on improvements efficacy of the treatments. The death rate was approximately in the acute efficacy of ECT with suprathreshold (eight to 0. Over the last half century, the mortality three NIMH-supported studies are discussed that examine from ECT has decreased dramatically because of a number the efficacy of maintenance therapies. Decreasing cognitive of advances, including the widespread use of modern anes side effects of ECT is another area of active research; changes thetic agents (e. Abrams put the risk of mortality from ECT into Cerletti and Bini (1) first investigated ECT as a treatment perspective in 1997. He noted that ECT was ten times safer for psychosis in 1938, theorizing that epilepsy and schizo- than childbirth and an order of magnitude less that the phrenia were incompatible. They hypothesized that the arti- spontaneous death rate in the population (9). McDonald: Department of Psychiatry and Behavioral Sci- treatment for severe melancholic depression. Four areas of ences, Emory University, Atlanta, Georgia research are important as we move into the twenty-first W. Vaughn McCall: Department of Psychiatry, Bowman Gray Medical century: developing a scientific understanding of the mecha- Center, Winston Salem, North Carolina Charles M. Epstein: Department of Neurology, Emory University, At- nisms of action of ECT, optimization of the efficacy of lanta, Georgia acute courses of ECT, treatment of the cognitive side effects 1098 Neuropsychopharmacology: The Fifth Generation of Progress of ECT, and continuing research into the efficacy of differ response to ECT was correlated with stimulation of the ent ECT techniques, including novel electrode placements deep brain structures that regulate the hypothalamic pitui and continuation/maintenance ECT. Stimulation of this system resulted in the release of pituitary hormones such as adreno corticotropin hormone (ACTH), thyrotropin, prolactin, MECHANISM OF ACTION OF ECT oxytocin, and vasopressin. Research using rodents adminis tered electroconvulsive shock (ECS) and examining the CSF Salzman asserts that the psychiatric community continues of patients receiving ECT has supported a relationship be- to show ambivalence toward ECT and ECT research has tween increases in neuropeptides during the convulsive suffered as a consequence (10). According to the diencephalic hypothesis, steps within the NIMH to address these issues and provide ECT seizures that have a longer duration, and ECT param more focused research in ECT (10), an understanding of eters that are more effective at stimulating the diencephalic the basic mechanisms by which ECT exerts its effect is still structures (i. This fact is an irony given that ECT is one of the and high-dose greater than low-dose ECT), therefore, few treatments in psychiatry that was theoretically based would be more effective in treating depression. Although the original hypothesis that epilepsy and Both of these assumptions have been questioned recently. Although the acute release of One of the most confusing aspects of accepting ECT as neuroendocrine markers did correlate with the type of sei a treatment for depression in the lay public and patients is zure administered and seizure duration, the expected corre the inability of clinicians to clearly explain how ECT is lation between the acute surge in plasma oxytocin, vasopres effective in relieving symptoms of depression. Patients have sin (19), or prolactin (20), and clinical response to ECT difficulty understanding how a treatment that is so seem was not shown in studies of depressed patients receiving a ingly toxic to the brain (i. ECT have focused less on the quantitative analysis of seizure However, the antidepressant medications have a number of duration and more on the relationship between a qualitative other effects on a variety of neurotransmitters, regulatory analysis of the ictal and postictal seizure morphology to hormones, and cellular mechanisms. ECT-induced seizures have a The mechanism by which a convulsive stimulus acts as characteristic pattern of hypersynchronous neuronal dis one of the most powerful antidepressants is equally complex charge with excitation of cortical neurons during the initial but the explanation may be as simplistic: ECT works by tonic phase, followed by alternating excitatory and inhibi increasing natural brain substances that decrease the excita tory effects in the clonic phase, and finally postictal suppres bility of the brain. The unique therapeutic action of ECT sion owing to inhibition and neuronal hypoexcitability. Seizure termination is an tered, and the stimulus waveform (23). A number of features active process that underlies the therapeutic mechanism of of the ictal EEG seizure that demonstrate a more intense the treatment. This idea is elaborated on in the following seizure predict clinical response to ECT. The initial finding was that an ECT seizure had to characteristics have been used to predict the efficacy of an continue for at least 25 seconds to be therapeutic (13) and ECT course (22,25–27), or more precisely these variables the patient had to accumulate a minimal number of seconds can be used to predict when a seizure is not adequate. Inade of EEG seizure time during a course of ECT (14). Chapter 76: Electroconvulsive Therapy 1099 Analysis of the EEG morphology has been used to deter- 1 minute and there is an active inhibitory process in the mine seizure intensity (26). Clinicians can be trained to interictal and postictal states evident by the development of visually inspect the EEG strips during ECT and determine slow or delta waves and decreases in the CBF and metabolic the adequacy of the seizure by evaluating the amplitude of uptake of glucose. The anticonvulsant properties of ECT the ictal EEG relative to baseline, symmetry of right and are hypothesized to occur because of enhanced transmission left hemispheric EEGs, distinct spike and wave pattern, and of inhibitory neurotransmitters and neuropeptides (e. Both the Thymatron GABA and endogenous opioid concentrations) and are an DGx ECT device (Somatics Inc. The magnitude of the seizure threshold increase is greater Although further testing of the clinical use of the computer- in more effective methods of administering ECT (i. Clinically, Sackeim in patients administered UL ECT, in determining if a sei cites unpublished data that the patients who return to an zure is adequate (24,27,29). However, nism of ECT is research correlating functional brain imag it is unclear whether the return of the seizure threshold to ing with response to ECT. Studies have shown an increase baseline occurs after an acute course of ECT in all patients in cerebral blood flow (CBF) up to 300% of baseline values or only in patients who relapse. The duration of the seizure with an accompanying increased permeability of the is also decreased over a series of treatments and is another blood–brain barrier and increased cerebral metabolic rate indication of the anticonvulsant effect of ECT. However, (CMR) up to 200% during the ictal period (30). In contrast, seizure duration is not related to efficacy unlike seizure CBF decreased to levels below baseline (31) or returned to threshold (43). Inhibitory processes include the early onset with clinical response, Nobler and colleagues (34) found a of high amplitude slow-wave activity after the tonic phase correlation between decreased CBF in the immediate postic of the seizure and bioelectric postictal suppression processes tal period and clinical response. The efficacy of ECT has been correlated included 54 depressed patients imaged using the Xenon with the early onset of these inhibitory processes, a fact that inhalation technique. Patients showed a low baseline CBF supports the anticonvulsant hypothesis. Two elements of compared to matched controls, and their response to ECT seizure expression, seizure strength and peak amplitude of was correlated with the further decrease in CBF from base- slow-wave activity, were inversely correlated with seizure line. These changes were greatest in the anterior cortical threshold and the third element, postictal bioelectric regions and the degree of change was correlated with clinical suppression, was not related to seizure threshold (40). Be- improvement on the Hamilton Depression Rating Scale. This finding provides the rationale Nobler and Sackeim (35) point out that decreased CBF in for developing EEG algorithms (see the preceding), increas the anterior cortex supports earlier findings by Max Fink ing the stimulus dosing or retitrating the seizure threshold (36,37) and their own group (38) of a relationship between during a course of ECT in patients who are not responding. There During a course of ECT, as in epilepsy, CBF/ CMR are additional data suggesting that the reductions in cerebral increase dramatically during the seizure and decrease below blood flow that occur immediately after ECT may persist baseline in the interictal and postictal states (35). Patients for days (39) to months (40) after the treatments and the responding to ECT show a more marked global decrease most dramatic reductions occurred in the frontal cortex. These changes were correlated with an increase findings with preclinical research in the anticonvulsant hy in the seizure threshold. Finally, increasing slow-wave activ pothesis as the mechanism of action of ECT (40). Both these finding and seizure duration decreases during the first several treat support the anticonvulsant hypothesis. ECT seizures usually are limited to less than The anticonvulsant hypothesis unifies many research 1100 Neuropsychopharmacology: The Fifth Generation of Progress findings and provides important new leads that have the reason for this apparent decline in efficacy is the increasing potential for improving clinical outcomes and predicting resistance to treatment among the patients referred for ECT patients who are at risk of relapsing after ECT. Prior to the development of the seroto vulsant properties of ECT related to clinical outcome in nin reuptake inhibitors (SSRIs), the most common reason clude an increase in the seizure threshold during a course of for referral for ECT was intolerance of available antidepres ECT, early onset of slow-wave activity interictally, distinct sant medications, chiefly tricyclic antidepressants (TCAs), postictal suppression, and decreases in CBF/CMR and in- and monoamine oxidase inhibitors (MAOIs).
The role of other serotonergic agents in during the first 3 weeks of treatment (188) 25mg indocin sale arthritis in hands and feet pictures. However cheap indocin 25 mg amex arthritis weight loss diet, a treating OCD including 5-HT3 agonists (ondansetron) and double-blind multicenter placebo-controlled trial of clona- 5-HT2 agonists requires further research generic indocin 50mg mastercard rheumatoid arthritis in your neck. Other benzodiaze- pines 25 mg indocin sale arthritis in neck relief, such as alprazolam, have also not shown efficacy in Noradrenergic Agents treating OCD (195). The noradrenergic system has also been explored as a novel individual pharmacotherapy in OCD. A case report of clon- idine, an 2-agonist, documented improvement in OCD Anticonvulsants (186). Intravenous clonidine was reported to markedly re- There are three case reports of significant response to non- duce obsessions in six OCD patients (187). However, in benzodiazepine-related anticonvulsants (two of whom had a double-blind controlled crossover trial of clomipramine, clinical epilepsy) all with carbamazepine, and 23 treatment clonazepam, and clonidine in 28 OCD patients, clonidine was found ineffective in reducing OCD symptoms (188). Two patients with OCD and clinical epilepsy responded to clonazepam treatment (196); however, clinical experience with anticonvulsants may be more positive. Two Stimulants and Dopamine Releasers of 12 patients (17%) at two sites had successful trials of Although most attention has focused on the blockade of carbamazepine, and six of 26 patients (23%) at three sites dopaminergic receptors in OCD, there are also reports that had positive outcomes with sodium valproate (172). Controlled trials are required, al- There have been six reported cases of improvement associ- though it has low abuse potential, low physical dependency, ated with antiandrogen treatment, four of which were men- and mild tolerance. Only one antiandro- gen failure has been reported, and one failure of estrogen treatment alone. An open trial with flutamide, an androgen AUTOIMMUNE TREATMENTS receptor antagonist, in eight OCD patients, demonstrated a lack of response (197). None of the OCD centers has Autoimmune mechanisms may also play a role in at least reported using this modality in treating OCD. As such, a subtype of patients with OCD, particularly those who this treatment has not been well studied. In practice, the manifest a sudden onset of OCD symptoms following infec- feminizing effects of these treatments in males limit their tion by group A B-hemolytic streptococci. In females, it is unclear whether penicillin were not found to be effective in such patients treatment efficacy, if present at all, is limited to specific (206). Plasmapheresis and intravenous immunoglobulin phases of the menstrual cycle. This treatment is unlikely to (IVIG) have been reported effective in case studies (207). Recently, both IVIG and plasma-exchange groups were as- sociated with significant improvement at 1 month in 30 children with infection-triggered exacerbations of OCD or Second Messenger SystemAgents tic disorders who received IVIG, plasma exchange, or pla- cebo (208). Agents that affect second messenger systems may also be effective in OCD. In a 6-week double-blind controlled crossover trial of inositol versus placebo in 13 OCD pa- tients, YBOCS scores with inositol treatment were signifi- INVASIVE PROCEDURES cantly lower than scores when on placebo (198). Finally, novel nonpharmacologic treatments may also play a role in treating some OCD patients. Right prefrontal re- Peptides petitive transcranial magnetic stimulation has been shown The role of peptide hormones has been studied in OCD. Further studies severity, suggesting a possible role for oxytocin in the neuro- are warranted. Recent work with vagal nerve stimulation, biology of OCD (199). Oxytocin is a hormone released by deep brain stimulation, and various forms of neurosurgery the posterior pituitary that regulates uterine and lactiferous suggest promise, but require controlled trials. It has been implicated in certain ritualized Patients who have failed all pharmacologic and behav- behaviors and the extinction of active avoidance behavior ioral treatments (and probably ECT) may be candidates for in animals (200). In all, there have been three reported cases neurosurgical treatments of OCD (210). Various proce- of improvement with chronic intranasal oxytocin and 12 dures in intractable cases have been successful, with 25% failures (172–201). There have been no reports of improve- to 30% of patients experiencing significant benefit without ment with vasopressin; however, this medication has not undue side effects. The most common current neurosurgical been administered chronically. None of eight patients at two procedure is cingulotomy, either performed via craniotomy OCD sites improved with oxytocin treatment. In a United States trial, 18 experience is limited with this modality, it does not appear patients underwent cingulotomy. At follow-up 2 years later, to be a promising treatment. Neurosurgery should be considered for a small percentage of truly refrac- Opiates tory patients. Warneke (202) reported that oral morphine in doses of 20 to 40 mg every 5 to 8 days produced marked benefit in five very severe cases of OCD. In contrast, naloxone has proved OCD SPECTRUM DISORDERS unsatisfactory and controversial (203,204). Tramadol, an analgesic that binds to opioid receptors and inhibits the An OCD spectrum has been proposed, consisting of various reuptake of norepinephrine and serotonin, has been re- disorders that overlap with OCD in several features, includ- ported to produce a significant decrease in Y-BOCS scores ing clinical symptoms (repetitive thoughts and behaviors), Chapter 114: Current and Experimental Therapeutics of OCD 1659 course of illness, comorbidity, family history, neurobiology, munomodulatory and invasive procedures have been ex- and treatment response (selective efficacy of SSRIs) (25). Three key clusters of disorders have been identified: (a) disorders with preoccupation with body image, body weight, or body sensations; (b) impulsive disorders in which ACKNOWLEDGMENTS repetitive behaviors are driven by pleasure; and (c) neurolog- ically based disorders with repetitive behaviors. Clusters 2 The authors acknowledge the support of the PBO Founda- and 3 are dealt with elsewhere in the volume. There is often poor insight or delusional convic- 1. Psychosocial function tion, and secondary depression and social phobia. A recent double-blind crossover trial compared the SRI 2. Diagnostic and Statistical Manual of Mental Disorders, fourth clomipramine to the noradrenergic reuptake inhibitor desi- ed. Washington, DC: American Psychiatric Association, 1994. Desipramine, the active control, was chosen to con- of obsessive-compulsive disorder in five US communities. Arch trol for nonspecific antidepressant and antidepressants, and Gen Psychiatry 1988;45:1094–1099. The epidemiology and differential because it has a similar side-effect profile to CMI, enhancing diagnosis of obsessive-compulsive disorder. The SRI CMI resulted in significantly greater 1994;55(Suppl):5–14. The prognostic significance of severity than did DMI, and also improved measures of func- obsessive-compulsive symptoms in schizophrenia. Subjects with delusional conviction regarding body der in patients with schizophrenia or schizoaffective disorder. Obsessive and like OCD, but in contrast to other mood or anxiety disor- compulsive symptoms in chronic schizophrenia. The delusional conviction in BDD appears disorder in patients with first-episode schizophrenia. Am J Psy- secondary to obsessive preoccupation, and also responds to chiatry 1999;156:1998–2000. Clozapine and obsession in patients with recent-onset schizophrenia and other psychotic disorders. Treatment of obsessive- compulsive syndromes in schizophrenia. Comorbidity of obses- In summary, SSRIs and the tricyclic antidepressant clomi- sive-compulsive disorder in bipolar disorder.