March 11, 2006

Patient perspective on bipolar disorder

Filed under: Drugs & Alcohol,Psychotic disorders — mental1 @ 8:04 pm

Bad Mother: I’m tempted to take up mountain climbing.

That K2 stat is worth remembering. Another number of dubious worth to be filed away in my head. Well written post.


Cannabis: Just who is likely to go mad?

Filed under: Drugs & Alcohol,Psychotic disorders — mental1 @ 7:54 pm

Reefer madness by Veronika Meduna | New Zealand Listener
Drug induced psychosis is a huge issue in psychiatry these days and this article is a very readable summary of the research that is happening around the COMT gene as part of the Queen Mary cohort research.
Maybe one day we’ll be able to sort out patients who are at increased risk. I’d love to know what the dominant phenotype is in our local populations. The sheer numbers make me wonder whether we have a large recessive population of valine-valine COMT people.

March 6, 2006

Zuclopenthixol acetate – just what is its role?

Filed under: Pharmacology,Psychotic disorders — mental1 @ 3:55 pm

Good old Accuphase.

It seems to have fallen out of favour on the ward at the moment. The main uses in the past were to sedate very unwell, very difficult [ie agitated and/or aggressive] psychotic or manic patients who needed more than the relatively short-acting droperidol [or now olanzapine] injection to control and manage them. Especially if oral meds are not an option for various reasons.
My clinical impression has been that the marked sedation that it gives seems to be of benefit and can often turn a patient around who is not responding. I’m not the only one with that impression. Nurses will often ask if Accuphase is indicated for a patient who just doesn’t seem to be responding, who is using their full quota of antipsychotic and benzo by the time the day is only half over and who is obviously unwell despite several days on the ward.
Is there any evidence for that though? Is it really worthwhile in this situation?Just what part of the drug is working on what? And just how much do you give? What part of the drug is providing the desired effect? Is it an antipsychotic effect as such or is the apparent improvement due to allowing the patient get a good nights sleep?

[Review] Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses RC Gibson, M Fenton, E da Silva Freire Coutinho, C Campbell The Cochrane Database of Systematic Reviews 2006 Issue 1 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: 10.1002/14651858.CD000525.pub2 This version first published online: 19 July 2004 in Issue 3, 2004 Date of Most Recent Substantive Amendment: 8 May 2004 This record should be cited as: Gibson RC, Fenton M, da Silva Freire Coutinho E, Campbell C. Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses. The Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD000525. DOI: 10.1002/14651858.CD000525.pub2. next Abstract Background Medication used for acute aggression in psychiatry must have rapid onset of effect, low frequency of administration and low levels of adverse effects. Zuclopenthixol acetate is said to have these properties. Objectives To estimate the clinical effects of zuclopenthixol acetate for the management of acute aggression or violence thought to be due to serious mental illnesses, in comparison to other drugs used to treat similar conditions. Search strategy We supplemented past searches of Current Controlled Trials (10/2000), the Cochrane Library (1997) and MEDLINE (1966-1997) and appeals for unpublished data with an update search of the Cochrane Schizophrenia Group’s Register of trials (September 2003). Selection criteria All randomised clinical trials involving people thought to have serious mental illnesses comparing zuclopenthixol acetate with other drugs. Data collection and analysis Data were extracted independently by two reviewers and cross-checked. We calculated fixed effects relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. Where possible, the number needed to treat/harm statistic (NNT/H) was calculated. We analyzed by intention-to-treat. Mean differences were used for continuous variables. Main results We found no data for the primary outcome, tranquilisation. Compared with haloperidol, zuclopenthixol acetate was no more sedating at two hours (n=40, 1 RCT, RR 0.60 CI 0.27 to 1.34). People given zuclopenthixol acetate were not at reduced risk of being given supplementary antipsychotics (n=134, 3 RCTs, RR 1.49 CI 0.97 to 2.30) although additional use of benzodiazepines was less (n=50, 1 RCT, RR 0.03 CI 0.00 to 0.47, NNT 2 CI 2 to 4). People given zuclopenthixol acetate had fewer injections over seven days compared with those allocated to haloperidol IM (n=70, 1 RCT, RR 0.39 CI 0.18 to 0.84, NNT 4 CI 3 to 14). We found no data on more episodes of aggression or harm to self or others. One trial (n=148) reported no significant difference in adverse effects for people receiving zuclopenthixol acetate compared with those allocated haloperidol at one, three and six days (RR 0.74 CI 0.43 to 1.27). Compared with haloperidol or clotiapine, people allocated zuclopenthixol did not seem to be at more risk of a range of movement disorders.

So Cochrane is not encouraging but the comparison is with haloperidol not olanzapine and the sedation at 12 or 24 hours is not mentioned.

Parenteral control of acute behavioural disturbance should be a last resort. Preferred options include the use of benzodiazepines in the short term: intramuscular (IM) lorazepam 1–2 mg (maximum 8 mg/day) is recommended, although it is not always available in Australia and may need to be specially requested; IM clonazepam 1–2 mg (maximum 6–8 mg/day) is in fairly common use; IM diazepam is used to a lesser extent, but, as it has a poor risk–benefit ratio in this form, its parenteral use is not recommended. Intramuscular olanzapine 10 mg (maximum 20 mg/day in this form; to be available soon in Australia) offers good efficacy with few unwanted side effects (E2).34 If such agents are unavailable or have failed, consideration can be given to IM administration of typical antipsychotics such as zuclopenthixol acetate (50–100 mg IM per 48 hours) or low-dose droperidol (5–20 mg; maximum 20 mg/day). Despite the common belief that intramuscular typical agents are ultimately effective in controlling acute behavioural disturbances, the evidence suggests that these agents may not demonstrate any particular benefit in terms of sedation and behavioural control over standard treatments.35 Furthermore, special caution should be exerted in using these agents, owing to their propensity to produce postural hypotension, EPS, and cardiotoxicity (especially droperidol in larger doses). Intramuscular haloperidol has limited application nowadays in Australia because of the significant adverse behavioural effects (eg, akathisia and other EPS, dysphoria, cognitive problems, decreased sense of wellbeing) associated with its use. Finally, as patients often dislike receiving typical antipsychotics parenterally, their use may adversely affect the therapeutic alliance between clinicians and patients.

This is an excerpt from Pharmacological approaches to the management of schizophrenia Timothy J R Lambert and David J Castle MJA 2003; 178 (9) Suppl 5 May: S57-S61.

So it is certainly not first line in the acute situation which is fair enough.

But that doesn’t answer my question about the hard to treat acutely unwell patient a few days down the line who is not responding to the usual options.

I suppose we need to look at what zuclo actually works on.

Zuclopenthixol is a cis(Z)-isomer of clopenthixol, a neuroleptic of the thioxanthene group. It has a high affinity for dopamine D1 and D2 receptors and a high affinity for α1-adrenergic and 5HT2 receptors.

Okay, so we are blocking the D1 and D2 receptors from becoming overstimulated.

What does dopamine do?

Too much causes hallucinations and paranoia [schizophrenia]. uncontrolled speech and movement [Tourette’s], agitation and repetitive action [OCD], over-excitement, euphoria and exaggerated convictions of ‘meaningfulness’ [mania]. Too little and you can get tremor and the inability to start voluntary movement [Parkinsons disease], feelings of meaninglessness, lethargy and misery[depression], catatonia and social withdrawal [negative schizophrenic symptoms, lack of attention and concentration [ADD] and cravings and withdrawal [addiction].

There are three main pathways, although these all interconnect.

The first one goes from the substantia nigra to the basal ganglia. These control automatic movement. Not enough dopamine and you get the Parkinsonian tremor and can’t get moving. There are then dopamine pathways going further out. The putamen goes to the premotor and motor cortex and too much dopamine can create physical tics.

The caudate nucleus connects to the orbital cortex which helps with higher order planning. Too much dopamine results in OCD type behaviour.
The basal ganglia-frontal lobe pathway is important in attention and consciousness. Not enough dopamine is implied in ADD, the negative symptoms of schizophrenia and the lethargy and mind numbing of depression.

The third pathway starts in the ventral tegmental nucleus in the midbrain. One part goes of to the locus coerulus which is the area that produces noradrenaline. Another part goes to the limbic system on the way to the olfactory bulb. A branch of this ends up in the frontal lobe. Too little dopamine is depressive and negative; too much is manic and positively schizophrenic.

Now there are 5 different subtypes of dopamine receptors but they can be loosely categroised into two groups. D1 and D5 are in the D1-like family. D1types increase CAMP and are excitatory.
D2,3,and 4 are in the D2-like family. These decrease cAMP and are inhibitory.

So zuclo is going to block D1 and D2 so you reduce the excitatory effect of the D1s and the inhibitory effect of the D2s. So which dopamine receptors are found where? And which receptors specifically amonst the D1 and 2 families.

OK, from a nice little lecture on dopamine receptors:

Cortex: D1,2,3,4,5

Limbic: D1,2,3,4,5

Striatum: D1,2

Pituitary: D2

Cardiovascular: D1,2

Time for a picture…

Dopamine pathways

An older article but a good one, Dopamine- mechanisms of action (Aust Prescr 1994;17:17-21) summarises the situation as follows:

D2 receptor subfamily Localisation and functions Postsynaptic D2 receptors are present in dopaminergic projection areas such as the striatum, limbic areas (nucleus accumbens, olfactory tubercle), hypothalamus and pituitary. D2 receptors are also located presynaptically in the substantia nigra pars compacta, ventral tegmental area and striatum, where they function to inhibit the release of dopamine. Activation of the striatal D2 receptor subfamily in rats results in a behavioural syndrome known as stereotypy, made up of repetitive sniffing and gnawing, accompanied by an increase in the animals’ activity. The repetitive behaviours observed in people following amphetamine ingestion may have a similar neurochemical basis. By contrast, blockade of the striatal D2 receptor subfamily produces marked increases in muscle rigidity in rats and a Parkinson-like syndrome in humans. In both rats and humans, administration of a D2 antagonist results in a rapid and large increase in prolactin release from the anterior pituitary, as dopamine’s inhibition of prolactin release is blocked. The D3 and D4 subtypes are much less abundant than the D2 subtype and have a different distribution. D3 receptors are located predominantly in limbic regions, with low concentrations in the striatum, whereas D4 receptors are found in the frontal cortex, amygdala, mid-brain and medulla. The effects mediated by these receptors are not known, although an autoreceptor (presynaptic) role has been suggested. Implications for therapy The effects elicited by dopamine agonists and antagonists are dependent on their selectivity. Selective drugs affect one subtype predominantly and therefore would be expected to have fewer adverse effects than nonselective drugs which have a wider spectrum of activity. A consideration of the D2 subfamily illustrates the potential therapeutic benefits of selective drug development. The D2 receptor subfamily has been implicated in the positive symptoms of schizophrenia, by the observation that the clinical potency of antipsychotic drugs is related to their affinity for the D2, not D1, receptorsubfamily. However, because receptors of the D2 subfamily are found in both limbic and striatal regions, theirblockade results respectively in both the desired reduction in psychosis and the unwanted appearance of Parkinson-like adverse effects. Blockade of D2 receptors which inhibit prolactin release results in increased plasma prolactin concentrations. The recent cloning and identification of the D3 receptor has attracted interest. Its localisation in the limbic areas suggests it may play a role in cognitive and emotional functions and so be an important target for antipsychotic drug therapy. This hypothesis is supported by findings that antipsychotic drugs previously thought to be selective for D2 receptors (raclopride and pimozide), as well as nonselective antipsychotic drugs (flupenthixol and chlorpromazine) and the atypical drug, clozapine, all interact with D3 receptors. If blockade of D3 receptors is involved in antipsychotic effects, then selective D3 antagonists may well provide antipsychotic drug therapy free from motor and hormonal adverse effects. Conversely, the use of dopamine agonists free of D3 activity in Parkinson’s disease would be predicted to reduce the incidence of psychosis-like adverse effects.

The most recently discovered member of the D2 subfamily, the D4 receptor, is also attracting interest for similar reasons. Of particular note are findings from a postmortem study which showed a 6-fold increase in D4 receptor binding in the brains of people diagnosed with schizophrenia compared vith controls. Clozapine has a 10-fold greater affinity for the D4 than the D2 receptor and this may be the basis of its antipsychotic action. Clozapine’s lack of extrapyramida adverse effects may be related to the fact that only low levels of D4 receptors are found in the striatum.

From this article Molecular Biology of the Dopamine Receptor Subtypes by Olivier Civelli :Neuroleptics usually act on D2.

D3 and 4 are common in the limbic system and much less in the nigrostriatal parts of the brain so this seems to fit with the psychiatric disorders rather than the movement disorders. D2 seems to have a stronger affinity for the neurolepts than D3 and D4 suggesting that despite the number of antipsychotic medications around, specific D3 and D4 affecting medications are relatively rare ie clozapine is the main one.
D4: Clozapine while binding to the D2 receptor is much more of a player at the D4 receptor and will bind to it in preference, suggesting that the D4 receptor is the key receptor in psychosis. D4 is relatively absent from the basal ganglia.

Okay, knowing all that…

What do the various antipsychotics act on?

Olanzapine (Zyprexa), 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3,-b][1,5,] benzodiazepine, is a newer antipsychotic agent of thienobenzodiazepine class. It has some structural similarities to clozapine. Olanzpine has an affinity to a number of receptors, including dopaminergic, serotonergic, adrenergic, histaminergic and muscarinic receptors. Olanzapine binds to the dopamine D1, D2, D3 and D4, with relatively high affinity to D4 (Seeman 1993). Olanzapine is more potent in binding to 5-HT 2A receptors compared to D2 receptors (Bymaster 1996). It also has a high affinity to 5-HT 2A, 5-HT 2C, 5-HT 3 receptors and moderate affinity to 5-HT 7 (Roth 1994, Bymaster 1996). [〈=pt&dblang=]

Which explains why olanzapine gives the clinical impression of being a damn good drug. It likes D4!

The thioxanthenes antagonise D1 so act on the nigrostriatal system.

So Accuphase probably doesn’t have the desired clinical response in the way I am looking for it due to this mechanism.

What about that serotonin receptor?

From Wikipedia…

Receptor Actions Agonists Antagonists
5-HT1A CNS: neuronal inhibition, behavioural effects (sleep, feeding, thermoregulation, anxiety) buspirone spiperone, methiothepin, ergotamine, yohimbine
5-HT1B CNS: presynaptic inhibition, behavioural effects; vascular: pulmonary vasoconstriction ergotamine, sumatriptan methiothepin, yohimbine, metergoline
5-HT1D CNS: locomotion; vascular: cerebral vasoconstriction sumatriptan methiothepin, yohimbine, metergoline, ergotamine
5-HT2A CNS: neuronal excitation, behavioural effects; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HT, LSD (CNS) ketanserin, cyproheptadine, pizotifen, LSD (PNS)
5-HT2B stomach: contraction α-methyl-5-HT, LSD (CNS) yohimbine, LSD (PNS)
5-HT2C CNS, choroid plexus: cerebrospinal fluid (CSF) secretion α-methyl-5-HT, agomelatine, LSD (CNS) mesulergine, agomelatine, LSD (PNS)
5-HT3 CNS, PNS: neuronal excitation, anxiety, emesis 2-methyl-5-HT metoclopramide (high doses), renzapride, ondansetron, alosetron, memantine
5-HT4 GIT, CNS: neuronal excitation, gastrointestinal motility 5-methoxytryptamine, metoclopramide, renzapride, tegaserod GR113808
5-HT5 CNS: unknown unknown unknown
5-HT6 CNS: unknown unknown unknown
5-HT7 CNS, GIT, blood vessels: unknown 5-carboxytryptamine, LSD methiothepin

Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor.

5HT2 is the one that antipsychotics seem to affect.

Time for a picture again though before I manage to confuse myself again…Serotonin receptors and drugs

Figure 13-8. Effects of psychoactive drugs on serotonergic neurotransmission. Drugs that act as agonists are indicated by solid-line arrows, whereas antagonists or inhibitors are shown with broken-line arrows. The 5-hydroxytryptamine (5-HT)1A receptor acts as both the somatodendritic autoreceptor and a postsynaptic receptor. Anxiolytic drugs, such as buspirone, are agonists at this receptor. In terminal fields, the autoreceptor is either the 5-HT1B or 5-HT1D subtype; these receptors also function as postsynaptic receptors. The antimigraine drug sumatriptan is an agonist at these receptors as well as at the 5-HT1F2A and 5-HT2C3 receptor, a ligand-gated ion channel, is blocked by drugs effective in the treatment of chemotherapy-induced nausea and emesis, such as ondansetron. Another important target for psychotherapeutic drugs is the serotonin transporter, which is blocked by drugs effective in the treatment of depression or obsessive-compulsive disorder, such as clomipramine. The enzyme responsible for the catabolism of serotonin, monoamine oxidase receptor. Hallucinogenic drugs, such as LSD, are agonists at 5-HT receptors, whereas atypical antipsychotic drugs, such as clozapine and olanzapine, are antagonists. The 5-HT(MAO), is inhibited by another class of antidepressants. MAOI, monoamine oxidase inhibitor; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor.

Hmm, does that mean I should be prescribing more cyproheptadine?

Too tired to think about that right now…I’ll leave that for another day.

March 2, 2006

Pharmacology: atypical antipsychotic off-label uses

This article interests me because antipsychotics can be very useful short term interventions due to sedative effects and their abilities to stop ruminating thoughts. When the usual sleep interventions don’t work, the sample box cupboard tends to be attacked. In this place offlabel use seems to be mostly for short term use for depression and anxiety. (more…)

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