Neurotransmitter transporters as targets of drug action
Classification and structure
Monoamine transporters (SLC6 gene family) as targets of psychotropic drugs
Other neurotransmitter transporters (SLC6 and SLC1 gene families) as targets of psychotropic drugs
Where are the transporters for histamine and neuropeptides?
Vesicular transporters: subtypes and function
Vesicular transporters (SLC18 gene family) as targets of psychotropic drugs
G-protein-linked receptors
Structure and function
G-protein-linked receptors as targets of psychotropic drugs
Enzymes as targets of psychotropic drugs
Cytochrome P450 drug metabolizing enzymes as targets of psychotropic drugs
Summary
Psychotropic drugs have many mechanisms of action, but they all target specific molecular sites that have profound effects upon neurotransmission. It is thus necessary to understand the anatomical infrastructure and chemical substrates of neurotransmission (Chapter 1) in order to grasp how psychotropic drugs work. Although there are over 100 essential psychotropic drugs utilized in clinical practice today (see Stahl’s Essential Psychopharmacology: the Prescriber’s Guide), there are only a few sites of action for all these therapeutic agents (Figure 2-1). Specifically, about a third of psychotropic drugs target one of the transporters for a neurotransmitter; another third target receptors coupled to G proteins; and perhaps only 10% target enzymes. All three of these sites of action will be discussed in this chapter. The balance of psychotropic drugs target various types of ion channels, which will be discussed in Chapter 3. Thus, mastering how just a few molecular sites regulate neurotransmission allows the psychopharmacologist to understand the theories about the mechanisms of action of virtually all psychopharmacological agents.
Figure 2-1. The molecular targets of psychotropic drugs. There are only a few major sites of action for the wide expanse of psychotropic drugs utilized in clinical practice. Approximately one-third of psychotropic drugs target one of the twelve-transmembrane-region transporters for a neurotransmitter (A), while another third target seven-transmembrane-region receptors coupled to G proteins (B). The sites of action for the remaining third of psychotropic drugs include enzymes (C), four-transmembrane-region ligand-gated ion channels (D), and six-transmembrane-region voltage-sensitive ion channels (E).
Neurotransmitter transporters as targets of drug action
Classification and structure
Neuronal membranes normally serve to keep the internal milieu of the neuron constant by acting as barriers to the intrusion of outside molecules and to the leakage of internal molecules. However, selective permeability of the membrane is required to allow discharge as well as uptake of specific molecules, to respond to the needs of cellular functioning. Good examples of this are neurotransmitters, which are released from neurons during neurotransmission and, in many cases, are also transported back into presynaptic neurons as a recapture mechanism following their release. This recapture – or reuptake – is done in order for neurotransmitter to be reused in a subsequent neurotransmission. Also, once inside the neuron, most neurotransmitters are transported again into synaptic vesicles for storage, protection from metabolism, and immediate use during a volley of future neurotransmission.
Both types of neurotransmitter transport – presynaptic reuptake as well as vesicular storage – utilize a molecular transporter belonging to a “superfamily” of twelve-transmembrane-region proteins (Figures 2-1A and 2-2). That is, neurotransmitter transporters have in common the structure of going in and out of the membrane 12 times (Figure 2-1A). These transporters are a type of receptor that binds to the neurotransmitter prior to transporting that neurotransmitter across the membrane.
Recently, details of the structures of neurotransmitter transporters have been determined; this has led to a proposed subclassification of neurotransmitter transporters. That is, there are two major subclasses of plasma membrane transporters for neurotransmitters. Some of these transporters are presynaptic and others are on glial membranes. The first subclass consists of sodium/chloride-coupled transporters, called the solute carrier SLC6 gene family, and includes transporters for the monoamines serotonin, norepinephrine, and dopamine (Table 2-1 and Figure 2-2A) as well as for the neurotransmitter GABA (gamma-aminobutyric acid) and the amino acid glycine (Table 2-2 and Figure 2-2A). The second subclass consists of high-affinity glutamate transporters, also called the solute carrier SLC1 gene family (Table 2-2 and Figure 2-2A).
Table 2-1 Presynaptic monoamine transporters
|
Transporter |
Common abbreviation |
Gene family |
Endogenous substrate |
False substrate |
|
Serotonin transporter |
SERT |
SLC6 |
Serotonin |
Ecstasy (MDMA) |
|
Norepinephrine transporter |
NET |
SLC6 |
Norepinephrine |
Dopamine |
|
Epinephrine |
||||
|
Amphetamine |
||||
|
Dopamine transporter |
DAT |
SLC6 |
Dopamine |
Norepinephrine |
|
Epinephrine |
||||
|
Amphetamine |
MDMA, 3,4-methylenedioxymethamphetamine
Table 2-2 Neuronal and glial GABA and amino acid transporters
|
Transporter |
Common abbreviation |
Gene family |
Endogenous substrate |
|
GABA transporter 1 (neuronal and glial) |
GAT1 |
SLC6 |
GABA |
|
GABA transporter 2 (neuronal and glial) |
GAT2 |
SLC6 |
GABA β-alanine |
|
GABA transporter 3 (mostly glial) |
GAT3 |
SLC6 |
GABA β-alanine |
|
GABA transporter 4, also called betaine transporter (neuronal and glial) |
GAT4 |
SLC6 |
GABA betaine |
|
BGT1 |
|||
|
Glycine transporter 1 (mostly glial) |
GlyT1 |
SLC6 |
Glycine |
|
Glycine transporter 2 (neuronal) |
GlyT2 |
SLC6 |
Glycine |
|
Excitatory amino acid transporters 1–5 |
EAAT1–5 |
SLC1 |
L-glutamate |
|
L-aspartate |
A. Sodium-potassium ATPase. Transport of many neurotransmitters into the presynaptic neuron is not passive, but rather requires energy. This energy is supplied by sodium-potassium ATPase (adenosine triphosphatase), an enzyme that is also sometimes referred to as the sodium pump. Sodium-potassium ATPase continuously pumps sodium out of the neuron, creating a downhill gradient. The “downhill” transport of sodium is coupled to the “uphill” transport of the neurotransmitter. In many cases this also involves cotransport of chloride and in some cases countertransport of potassium. Examples of neurotransmitter transporters include the serotonin transporter (SERT), the norepinephrine transporter (NET), the dopamine transporter (DAT), the GABA transporter (GAT), the glycine transporter (GlyT), and the excitatory amino acid transporter (EAAT).
B. Vesicular transporters. Vesicular transporters package neurotransmitters into synaptic vesicles through the use of a proton ATPase, or proton pump. The proton pump utilizes energy to pump positively charged protons continuously out of the synaptic vesicle. Neurotransmitter can then be transported into the synaptic vesicle, keeping the charge inside the vesicle constant. Examples of vesicular transporters include the vesicular monoamine transporter (VMAT2), which transports serotonin, norepinephrine, dopamine, and histamine; the vesicular acetylcholine transporter (VAChT), which transports acetylcholine; the vesicular inhibitory amino acid transporter (VIAAT), which transports GABA; and the vesicular glutamate transporter (VGluT), which transports glutamate.
Figure 2-2
In addition, there are three subclasses of intracellular synaptic vesicle transporters for neurotransmitters. The SLC18 gene family comprises the vesicular monoamine transporters (VMATs) for serotonin, norepinephrine, dopamine, and histamine and the vesicular acetylcholine transporter (VAChT). The SLC32 gene family consists of the vesicular inhibitory amino acid transporters (VIAATs). Finally, the SLC17 gene family consists of the vesicular glutamate transporters, such as VGluT1–3 (Table 2-3 and Figure 2-2B).
Table 2-3 Vesicular neurotransmitter transporters
|
Transporter |
Common abbreviation |
Gene family |
Endogenous substrate |
|
Vesicular monoamine transporters 1 and 2 |
VMAT1 |
SLC18 |
Serotonin |
|
VMAT2 |
Norepinephrine |
||
|
Dopamine |
|||
|
Vesicular acetylcholine transporter |
VAChT |
SLC18 |
Acetylcholine |
|
Vesicular inhibitory amino acid transporter |
VIAAT |
SLC32 |
GABA |
|
Vesicular glutamate transporters 1–3 |
VGluT1–3 |
SLC17 |
Glutamate |
Monoamine transporters (SLC6 gene family) as targets of psychotropic drugs
Reuptake mechanisms for monoamines utilize unique presynaptic transporters (Figure 2-2A) but the same vesicular transporter in all three monoamine neurons (histamine neurons also use the same vesicular transporter) (Figure 2-2B). That is, the unique presynaptic transporter for serotonin is known as SERT, for norepinephrine is known as NET, and for dopamine is known as DAT (Table 2-1 and Figure 2-2A). All three of these monoamines are then transported into synaptic vesicles of their respective neurons by the same vesicular transporter, known as VMAT2 (vesicular monoamine transporter 2) (Figure 2-2B and Table 2-3).
Although the three presynaptic transporters – SERT, NET, and DAT – are unique in their amino acid sequences and binding affinities for monoamines, each presynaptic monoamine transporter nevertheless has appreciable affinity for amines other than the one matched to its own neuron (Table 2-1). Thus, if other transportable neurotransmitters or drugs are in the vicinity of a given monoamine transporter, they may also be transported into the presynaptic neuron by hitchhiking a ride on certain transporters that can carry them into the neuron.
For example, the norepinephrine transporter (NET) has high affinity for the transport of dopamine as well as for norepinephrine, the dopamine transporter (DAT) has high affinity for the transport of amphetamines as well as for dopamine, and the serotonin transporter (SERT) has high affinity for the transport of “ecstasy” (the drug of abuse MDMA or 3,4-methylenedioxymethamphetamine) as well as for serotonin (Table 2-1).
How are neurotransmitters transported? Monoamines are not passively shuttled into the presynaptic neuron, because it requires energy to concentrate monoamines into a presynaptic neuron. That energy is provided by transporters in the SLC6 gene family coupling the “downhill” transport of sodium (down a concentration gradient) with the “uphill” transport of the monoamine (up a concentration gradient) (Figure 2-2A). Thus, the monoamine transporters are really sodium-dependent cotransporters; in most cases, this involves the additional cotransport of chloride, and in some cases the countertransport of potassium. All of this is made possible by coupling monoamine transport to the activity of sodium-potassium ATPase (adenosine triphosphatase), an enzyme sometimes called the “sodium pump” that creates the downhill gradient for sodium by continuously pumping sodium out of the neuron (Figure 2-2A).
The structure of a monoamine transporter from the SLC6 family has recently been proposed to have binding sites not only for the monoamine, but also for two sodium ions (Figure 2-2A). In addition, these transporters may exist as dimers, or two copies working together with each other, but the manner in which they cooperate is not yet well understood and is not shown in the figures. There are other sites on this transporter – not well defined – for drugs such as antidepressants, which bind to the transporter and inhibit reuptake of monoamines but do not bind to the substrate site and are not transported into the neuron (thus they are allosteric, meaning “other site”).
In the absence of sodium, there is low affinity of the monoamine transporter for its monoamine substrate, and thus binding of neither sodium nor monoamine. An example of this is shown for the serotonin transporter SERT in Figure 2-2A, where some of the transport “wagons” have flat tires, indicating no binding of sodium as well as absence of binding of serotonin to its substrate binding site, since the transporter has low affinity for serotonin in the absence of sodium. The allosteric site for antidepressant binding is also empty (the front seat in Figure 2-2A). However, in the presence of sodium ions, the tires are “inflated” by sodium binding and serotonin can also bind to its substrate site on SERT. The situation is now primed for serotonin transport back into the serotonergic neuron, along with cotransport of sodium and chloride down the gradient and into the neuron and countertransport of potassium out of the neuron (Figure 2-2A). But if a drug binds to an inhibitory allosteric site on SERT, this reduces the affinity of the serotonin transporter SERT for its substrate serotonin, and serotonin binding is prevented.
Why does this matter? Blocking the presynaptic monoamine transporter has a huge impact on neurotransmission at any synapse that utilizes that neurotransmitter. The normal recapture of neurotransmitter by the presynaptic neurotransmitter transporter in Figure 2-2A keeps the levels of this neurotransmitter from accumulating in the synapse. Normally, following release from the presynaptic neuron, neurotransmitters only have time for a brief dance on their synaptic receptors, and the party is soon over because the monoamines climb back into the presynaptic neuron on their transporters (Figure 2-2A). If one wants to enhance normal synaptic activity of these neurotransmitters, or restore their diminished synaptic activity, this can be accomplished by blocking these transporters. Although this might not seem to be a very dramatic thing, the fact is that this alteration in chemical neurotransmission – namely the enhancement of synaptic monoamine action – is thought to underlie the clinical effects of all the agents that block monoamine transporters, including most known antidepressants and stimulants. Specifically, many antidepressants enhance serotonin, norepinephrine, or both, due to actions on SERT and/or NET. Some antidepressants act on DAT, as do stimulants. Also, recall that many antidepressants that block monoamine transporters are also effective anxiolytics, reduce neuropathic pain, and have additional therapeutic actions as well. Thus, it may come as no surprise that drugs that block monoamine transporters are among the most frequently prescribed psychotropic drugs. In fact, about a third of the currently prescribed essential psychotropic drugs act by targeting one or more of the three monoamine transporters.
Other neurotransmitter transporters (SLC6 and SLC1 gene families) as targets of psychotropic drugs
In addition to the three transporters for monoamines discussed in detail above, there are several other transporters for various different neurotransmitters or their precursors. Although this includes a dozen additional transporters, there is only one psychotropic drug used clinically that is known to bind to any of these transporters. Thus, there is a presynaptic transporter for choline, the precursor to the neurotransmitter acetylcholine, but no known drugs target this transporter. There are also several transporters for the ubiquitous inhibitory neurotransmitter GABA, known as GAT1–4 (Table 2-2). Although debate continues about the exact localization of these subtypes at presynaptic neurons, neighboring glia, or even postsynaptic neurons, it is clear that a key presynaptic transporter of GABA is the GAT1 transporter, which is selectively blocked by the anticonvulsant tiagabine, thereby increasing synaptic GABA concentrations. In addition to anticonvulsant actions, this increase in synaptic GABA may have therapeutic actions in anxiety, sleep disorders, and pain. No other inhibitors of this transporter are available for clinical use.
Finally, there are multiple transporters for two amino acid neurotransmitters, glycine and glutamate (Table 2-2). There are no drugs utilized in clinical practice that are known to block glycine transporters, although new agents are in clinical trials for treating schizophrenia. The glycine transporters, along with the choline and GABA transporters, are all members of the same family to which the monoamine transporters belong and have a similar structure (Figure 2-2A, Tables 2-1 and 2-2). However, the glutamate transporters belong to a unique family, SLC1, and have a unique structure and somewhat different functions compared to those transporters of the SLC6 family (Table 2-2).
Specifically, there are several transporters for glutamate, known as excitatory amino acid transporters 1–5, or EAAT1–5 (Table 2-2). The exact localization of these various transporters at presynaptic neurons, postsynaptic neurons, or glia is still under investigation, but the uptake of glutamate into glia is well known to be a key system for recapturing glutamate for reuse once it has been released. Transport into glia results in conversion of glutamate into glutamine, and then glutamine enters the presynaptic neuron for reconversion back into glutamate. No drugs utilized in clinical practice are known to block glutamate transporters.
One difference between transport of neurotransmitters by the SLC6 gene family and transport of glutamate by the SLC1 gene family is that glutamate does not seem to cotransport chloride with sodium when it also cotransports glutamate. Also, glutamate transport is almost always characterized by the countertransport of potassium, whereas this is not always the case with SLC6 gene family transporters. Glutamate transporters may work together as trimers rather than dimers, as the SLC6 transporters seem to do. The functional significance of these differences remains obscure, but may become more apparent if clinically useful psychopharmacologic agents that target glutamate transporters are discovered. Since it may often be desirable to diminish rather than enhance glutamate neurotransmission, the future utility of glutamate transporters as therapeutic targets is also unclear.
Where are the transporters for histamine and neuropeptides?
It is an interesting observation that apparently not all neurotransmitters are regulated by reuptake transporters. The central neurotransmitter histamine apparently does not have a presynaptic transporter (although it is transported into synaptic vesicles by VMAT2, the same transporter used by the monoamines – see Figure 2-2B). Histamine’s inactivation is thus thought to be entirely enzymatic. The same can be said for neuropeptides, since reuptake pumps and presynaptic transporters have not been found for them, and are thus thought to be lacking for this class of neurotransmitter. Inactivation of neuropeptides is apparently by diffusion, sequestration, and enzymatic destruction, but not by presynaptic transport. It is always possible that a transporter will be discovered in the future for some of these neurotransmitters, but at the present time there are no known presynaptic transporters for either histamine or neuropeptides.
Vesicular transporters: subtypes and function
Vesicular transporters for the monoamines (VMATs) are members of the SLC18 gene family and have already been discussed above. They are shown in Figure 2-2B and listed in Table 2-3, as is the vesicular transporter for acetylcholine – also a member of the SLC18 gene family but known as VAChT. The GABA vesicular transporter is a member of the SLC32 gene family and is called VIAAT (vesicular inhibitory amino acid transporter; Figure 2-2Band Table 2-3). Finally, vesicular transporters for glutamate, called vGluT1–3 (vesicular glutamate transporters 1, 2, and 3) are members of the SLC17 gene family – and are also shown in Figure 2-2B and listed in Table 2-3. The SV2A transporter is a novel twelve-transmembrane-region synaptic vesicle transporter of uncertain mechanism and with unclear substrates; it is localized within the synaptic vesicle membrane and binds the anticonvulsant levetiracetam, perhaps interfering with neurotransmitter release and thereby reducing seizures.
How do neurotransmitters get inside synaptic vesicles? In the case of vesicular transporters, storage of neurotransmitters is facilitated by a proton ATPase, known as the “proton pump,” that utilizes energy to pump positively charged protons continuously out of the synaptic vesicle (Figure 2-2B). The neurotransmitters can then be concentrated against a gradient by substituting their own positive charge inside the vesicle for the positive charge of the proton being pumped out. Thus, neurotransmitters are not so much transported as “antiported” – i.e., they go in while the protons are actively transported out, keeping charge inside the vesicle constant. This concept is shown in Figure 2-2B for the VMAT transporting dopamine in exchange for protons. Contrast this with Figure 2-2A, where a monoamine transporter on the presynaptic membrane is cotransporting a monoamine along with sodium and chloride, but with the help of a sodium-potassium ATPase (sodium pump) rather than a proton pump.
Vesicular transporters (SLC18 gene family) as targets of psychotropic drugs
Vesicular transporters for acetylcholine (SLC18 gene family), GABA (SLC32 gene family), and glutamate (SLC17 gene family) are not known to be targeted by any drug utilized by humans. However, vesicular transporters for monoamines in the SLC18 gene family, or VMATs, particularly those in dopamine and norepinephrine neurons, are potently targeted by several drugs including amphetamine, tetrabenazine, and reserpine. Amphetamine thus has two targets: monoamine transporters as well as VMATs. In contrast, other stimulants such as methylphenidate and cocaine target only the monoamine transporters, and in much the same manner as described for antidepressants (see Chapter 7).
G-protein-linked receptors
Structure and function
Another major target of psychotropic drugs is the class of receptors linked to G proteins. These receptors all have the structure of seven transmembrane regions, meaning that they span the membrane seven times (Figure 2-1). Each of the transmembrane regions clusters around a central core that contains a binding site for a neurotransmitter. Drugs can interact at this neurotransmitter binding site or at other sites (allosteric sites) on the receptor. This can lead to a wide range of modifications of receptor actions due to mimicking or blocking, partially or fully, the neurotransmitter function that normally occurs at this receptor. These drug actions can thus change downstream molecular events such as which phosphoproteins are activated or inactivated and therefore which enzymes, receptors, or ion channels are modified by neurotransmission. Such drug actions can also change which genes are expressed, and thus which proteins are synthesized and which functions are amplified, from synaptogenesis, to receptor and enzyme synthesis, to communication with downstream neurons innervated by the neuron with the G-protein-linked receptor.
These actions on neurotransmission by G-protein-linked receptors are described in detail in Chapter 1 on signal transduction and chemical neurotransmission. The reader should have a good command of the function of G-protein-linked receptors and their role in signal transduction from specific neurotransmitters, as described in Chapter 1, in order to understand how drugs acting at G-protein-linked receptors modify the signal transduction that arises from these receptors. This is important to understand because such drug-induced modifications in signal transduction from G-protein-linked receptors can have profound actions on psychiatric symptoms. In fact, the single most common action of psychotropic drugs utilized in clinical practice is to modify the actions of G-protein-linked receptors, resulting in either therapeutic actions or side effects. Here we will describe how various drugs stimulate or block these receptors, and throughout the textbook we will show how specific drugs acting at specific G-protein-linked receptors have specific actions on specific psychiatric disorders.
G-protein-linked receptors as targets of psychotropic drugs
G-protein-linked receptors are a large superfamily of receptors that interact with many neurotransmitters and with many psychotropic drugs (Figure 2-1B). There are numerous ways to subtype these receptors, but pharmacologic subtypes are perhaps the most important to understand for clinicians who wish to target specific receptors with psychotropic drugs utilized in clinical practice. That is, the natural neurotransmitter interacts at all of its receptor subtypes, but many drugs are more selective than the neurotransmitter itself for certain receptor subtypes and thus define a pharmacologic subtype of receptor at which they specifically interact. This is not unlike the concept of the neurotransmitter being a master key that opens all the doors, and a drug that interacts at pharmacologically specific receptor subtypes functioning as a specific key opening only one door. Here we will develop the concept that drugs have many different ways of interacting at pharmacologic subtypes of G-protein-linked receptors, which occur across an agonist spectrum (Figure 2-3).
Figure 2-3. Agonist spectrum. Shown here is the agonist spectrum. Naturally occurring neurotransmitters stimulate receptors and are thus agonists. Some drugs also stimulate receptors and are therefore agonists as well. It is possible for drugs to stimulate receptors to a lesser degree than the natural neurotransmitter; these are called partial agonists or stabilizers. It is a common misconception that antagonists are the opposite of agonists because they block the actions of agonists. However, although antagonists prevent the actions of agonists, they have no activity of their own in the absence of the agonist. For this reason, antagonists are sometimes called “silent.” Inverse agonists, on the other hand, do have opposite actions compared to agonists. That is, they not only block agonists but can also reduce activity below the baseline level when no agonist is present. Thus, the agonist spectrum reaches from full agonists to partial agonists through to “silent” antagonists and finally inverse agonists.
No agonist
An important concept for the agonist spectrum is that the absence of agonist does not necessarily mean that nothing is happening with signal transduction at G-protein-linked receptors. Agonists are thought to produce a conformational change in G-protein-linked receptors that leads to full receptor activation, and thus full signal transduction. In the absence of agonist, this same conformational change may still be occurring at some receptor systems, but only at very low frequency. This is referred to as constitutive activity, which may be present especially in receptor systems and brain areas where there is a high density of receptors. Thus, when something occurs at very low frequency but among a high number of receptors, it can still produce detectable signal transduction output. This is represented as a small – but not absent – amount of signal transduction in Figure 2-4.
Figure 2-4. Constitutive activity. The absence of agonist does not mean that there is no activity related to G-protein-linked receptors. Rather, in the absence of agonist, the receptor’s conformation is such that it leads to a low level of activity, or constitutive activity. Thus, signal transduction still occurs, but at a low frequency. Whether this constitutive activity leads to detectable signal transduction is affected by the receptor density in that brain region.
Agonists
An agonist produces a conformational change in the G-protein-linked receptor that turns on the synthesis of second messenger to the greatest extent possible (i.e., the action of a full agonist). The full agonist is generally represented by the naturally occurring neurotransmitter itself, although some drugs can also act in as full a manner as the natural neurotransmitter. What this means from the perspective of chemical neurotransmission is that the full array of downstream signal transduction is triggered by a full agonist (Figure 2-5). Thus, downstream proteins are maximally phosphorylated, and genes are maximally impacted. Loss of the agonist actions of a neurotransmitter at G-protein-linked receptors, due to deficient neurotransmission of any cause, would lead to the loss of this rich downstream chemical tour de force. Thus, agonists that restore this natural action would be potentially useful in states where reduced signal transduction leads to undesirable symptoms.
Figure 2-5. Full agonist: maximum signal transduction. When a full agonist binds to G-protein-linked receptors, it causes conformational changes that lead to maximum signal transduction. Thus, all the downstream effects of signal transduction, such as phosphorylation of proteins and gene activation, are maximized.
There are two major ways to stimulate G-protein-linked receptors with full agonist action. First, several drugs directly bind to the neurotransmitter site and produce the same array of signal transduction effects as a full agonist (Table 2-4). These are direct-acting agonists. Second, many drugs can indirectly act to boost the levels of the natural full agonist neurotransmitter (Table 2-5). This happens when neurotransmitter inactivation mechanisms are blocked. The most prominent examples of indirect full agonist actions have already been discussed above, namely inhibition of the monoamine transporters SERT, NET, and DAT and the GABA transporter GAT1. Another way to accomplish indirect full agonist action is to block the enzymatic destruction of neurotransmitters (Table 2-5). Two examples of this are inhibition of the enzymes monoamine oxidase (MAO) and acetylcholinesterase.
Table 2-4 Key G-protein-linked receptors directly targeted by psychotropic drugs
|
Neurotransmitter |
G-protein receptor and pharmacologic subtype directly targeted |
Pharmacologic action |
Drug class |
Therapeutic action |
|
Dopamine |
D2 |
Antagonist or partial agonist |
Conventional antipsychotic; atypical antipsychotic |
Antipsychotic; antimanic |
|
Serotonin |
5HT2A |
Antagonist or inverse agonist |
Atypical antipsychotic |
Reduced motor side effects; possible mood stabilizing and antidepressant actions in bipolar disorder |
|
Antidepressant, hypnotic |
Improve mood and insomnia |
|||
|
5HT1A |
Antagonist or partial agonist |
Atypical antipsychotic |
Unknown secondary receptor actions, possibly contributing to efficacy and tolerability |
|
|
5HT1A |
Partial agonist |
Anxiolytic |
Anxiolytic; booster of antidepressant action |
|
|
Norepinephrine |
Alpha2 |
Antagonist |
Antidepressant |
Antidepressant |
|
Agonist |
Antihypertensive |
Cognition and behavioral disturbance in attention deficit hyperactivity disorder |
||
|
Alpha1 |
Antagonist |
Many antipsychotics and antidepressants |
Side effects of orthostatic hypotension and possibly sedation |
|
|
GABA |
GABAB |
Agonist |
Gamma hydroxybutyrate/sodium oxybate |
Cataplexy, sleepiness in narcolepsy; possible enhanced slow-wave sleep and pain reduction |
|
Melatonin |
MT1 |
Agonist |
Hypnotic |
Improve insomnia |
|
MT2 |
Agonist |
Hypnotic |
Improve insomnia |
|
|
Histamine |
H1 |
Antagonist |
Many antipsychotics and antidepressants; some anxiolytics |
Therapeutic effect for anxiety and insomnia; side effect of sedation and weight gain |
|
Acetylcholine |
M1 |
Antagonist |
Many antipsychotics and antidepressants |
Side effects of memory disturbance, sedation, dry mouth, blurred vision, constipation, urinary retention |
|
M3/M5 |
Antagonist |
Some atypical antipsychotics |
May contribute to metabolic dysregulation (dyslipidemia and diabetes) |
Table 2-5 Key G-protein-linked receptors indirectly targeted by psychotropic drugs
|
Neurotransmitter |
G-protein receptor and pharmacologic subtype indirectly targeted |
Pharmacologic action |
Drug class |
Therapeutic action |
|
Dopamine |
D1 and D2 (possibly D3, D4) |
Agonist via increasing dopamine itself at all dopamine receptors |
Stimulant (actions at dopamine and/or synaptic vesicle transporters DAT and VMAT2) |
Improvement of attention deficit hyperactivity disorder (ADHD) |
|
Antidepressant (actions at dopamine and/or norepinephrine transporters DAT and/or NET) |
Antidepressant; ADHD |
|||
|
MAO inhibitor (reducing dopamine metabolism) |
Antidepressant |
|||
|
Serotonin |
5HT1A (presynaptic somadendritic autoreceptors) |
Agonist via increasing serotonin itself at all serotonin receptors |
Antidepressant (actions at serotonin transporters SERT) |
Antidepressant; anxiolytic |
|
5HT2A postsynaptic receptors; possibly 5HT1A, 5HT2C, 5HT6, 5HT7 postsynaptic receptors |
||||
|
MAO inhibitor (reducing serotonin metabolism) |
Antidepressant |
|||
|
Norepinephrine |
Beta2 postsynaptic; possibly alpha2presynaptic and postsynaptic |
Agonist via increasing norepinephrine itself at all norepinephrine receptors |
Antidepressant; neuropathic pain (actions at norepinephrine transporter NET) |
Antidepressant; improve ADHD; for chronic pain (when combined with SERT inhibition) |
|
MAO inhibitor (reducing norepinephrine metabolism) |
Antidepressant |
|||
|
GABA |
GABAA and GABAB |
Agonist via increasing GABA itself at all GABA receptors |
Anticonvulsant (actions at the GABA GAT1 transporter) |
Anticonvulsant; possibly anxiolytic, for chronic pain, for slow-wave sleep |
|
Acetylcholine |
M1 (possibly M2–M5) |
Agonist via increasing acetylcholine itself at all acetylcholine receptors |
Acetylcholinesterase inhibitor (reducing acetylcholine metabolism) |
Slowing progression in Alzheimer’s disease |
DAT, dopamine transporter; MAO, monoamine oxidase; NET, norepinephrine transporter; SERT, serotonin transporter; VMAT, vesicular monoamine transporter.
Antagonists
On the other hand, it is also possible that full agonist action can be too much of a good thing and that maximal activation of the signal transduction cascade is not always desirable, as in states of overstimulation by neurotransmitters. In such cases, blocking the action of the natural neurotransmitter agonist may be desirable. This is the property of an antagonist. Antagonists produce a conformational change in the G-protein-linked receptor that causes no change in signal transduction – including no change in whatever amount of any constitutive activity that may have been present in the absence of agonist (compare Figure 2-4 with Figure 2-6). Thus, true antagonists are “neutral” and, since they have no actions of their own, are also called “silent.”
Figure 2-6. “Silent” antagonist. An antagonist blocks agonists (both full and partial) from binding to G-protein-linked receptors, thus preventing agonists from causing maximum signal transduction and instead changing the receptor’s conformation back to the same state as exists when no agonist is present. Antagonists also reverse the effects of inverse agonists, again by blocking the inverse agonists from binding and then returning the receptor conformation to the baseline state. Antagonists do not have any impact on signal transduction in the absence of an agonist.
There are many more examples in clinical practice of important antagonists of G-protein-linked receptors than there are of direct-acting full agonists (Table 2-4). Antagonists are well known both as the mediators of therapeutic actions in psychiatric disorders and as the cause of undesirable side effects (Table 2-4). Some of these may prove to be inverse agonists (see below), but most antagonists utilized in clinical practice are characterized simply as “antagonists.”
Antagonists block the actions of everything in the agonist spectrum (Figure 2-3). In the presence of an agonist, an antagonist will block the actions of that agonist but does nothing itself (Figure 2-6). The antagonist simply returns the receptor conformation back to the same state as exists when no agonist is present (Figure 2-4). Interestingly, an antagonist will also block the actions of a partial agonist. Partial agonists are thought to produce a conformational change in the G-protein-linked receptor that is intermediate between a full agonist and the baseline conformation of the receptor in the absence of agonist (Figures 2-7 and 2-8). An antagonist reverses the action of a partial agonist by returning the G-protein-linked receptor to the same conformation (Figure 2-6) as exists when no agonist is present (Figure 2-4). Finally, an antagonist reverses an inverse agonist. Inverse agonists are thought to produce a conformational state of the receptor that totally inactivates it and even removes the baseline constitutive activity (Figure 2-9). An antagonist reverses this back to the baseline state that allows constitutive activity (Figure 2-6), the same as exists for the receptor in the absence of the neurotransmitter agonist (Figure 2-4).
By themselves, therefore, it is easy to see that true antagonists have no activity, and why they are sometimes referred to as “silent.” Silent antagonists return the entire spectrum of drug-induced conformational changes in the G-protein-linked receptor (Figures 2-3 and 2-10) to the same place (Figure 2-6) – i.e., the conformation that exists in the absence of agonist (Figure 2-4).
Partial agonists
It is possible to produce signal transduction that is something more than an antagonist yet something less than a full agonist. Turning down the gain a bit from full agonist actions, but not all the way to zero, is the property of a partial agonist (Figure 2-7). This action can also be seen as turning up the gain a bit from silent antagonist actions, but not all the way to a full agonist. Depending upon how close this partial agonist is to a full agonist or to a silent antagonist on the agonist spectrum will determine the impact of a partial agonist on downstream signal transduction events.
Figure 2-7. Partial agonist. Partial agonists stimulate G-protein-linked receptors to enhance signal transduction but do not lead to maximum signal transduction the way full agonists do. Thus, in the absence of a full agonist, partial agonists increase signal transduction. However, in the presence of a full agonist, the partial agonist will actually turn down the strength of various downstream signals. For this reason, partial agonists are sometimes referred to as stabilizers.
The amount of “partiality” that is desired between agonist and antagonist – that is, where a partial agonist should sit on the agonist spectrum – is a matter of debate as well as trial and error. The ideal therapeutic agent may have signal transduction through G-protein-linked receptors that is not too “hot,” yet not too “cold,” but “just right,” sometimes called the “Goldilocks” solution. Such an ideal state may vary from one clinical situation to another, depending upon the balance between full agonism and silent antagonism that is desired.
In cases where there is unstable neurotransmission throughout the brain, such as when pyramidal neurons in the prefrontal cortex are out of “tune,” it may be desirable to find a state of signal transduction that stabilizes G-protein-linked receptor output somewhere between too much and too little downstream action. For this reason, partial agonists are also called “stabilizers,” since they have the theoretical capacity to find a stable solution between the extremes of too much full agonist action and no agonist action at all (Figure 2-7).
Since partial agonists exert an effect less than that of a full agonist, they are also sometimes called “weak,” with the implication that partial agonism means partial clinical efficacy. That is certainly possible in some cases, but it is more sophisticated to understand the potential stabilizing and “tuning” actions of this class of therapeutic agents, and not to use terms that imply clinical actions for the entire class of drugs that may only apply to some individual agents. A few partial agonists are utilized in clinical practice (Table 2-4) and more are in clinical development.
Light and dark as an analogy for partial agonists
It was originally conceived that a neurotransmitter could only act at receptors like a light switch, turning things on when the neurotransmitter is present and turning things off when the neurotransmitter is absent. We now know that many receptors, including the G-protein-linked receptor family, can function rather more like a rheostat. That is, a full agonist will turn the lights all the way on (Figure 2-8A), but a partial agonist will only turn the light on partially (Figure 2-8B). If neither full agonist nor partial agonist is present, the room is dark (Figure 2-8C).
Figure 2-8. Agonist spectrum: rheostat. A useful analogy for the agonist spectrum is a light controlled by a rheostat. The light will be brightest after a full agonist turns the light switch fully on (A). A partial agonist will also act as a net agonist and turn the light on, but only partially, according to the level preset in the partial agonist’s rheostat (B). If the light is already on, a partial agonist will “dim” the lights, thus acting as a net antagonist. When no full or partial agonist is present, the situation is analogous to the light being switched off (C).
Each partial agonist has its own set point engineered into the molecule, such that it cannot turn the lights on brighter even with a higher dose. No matter how much partial agonist is given, only a certain degree of brightness will result. A series of partial agonists will differ one from the other in the degree of partiality, so that theoretically all degrees of brightness can be covered within the range from “off” to “on,” but each partial agonist has its own unique degree of brightness associated with it.
What is so interesting about partial agonists is that they can appear as a net agonist, or as a net antagonist, depending upon the amount of naturally occurring full agonist neurotransmitter that is present. Thus, when a full agonist neurotransmitter is absent, a partial agonist will be a net agonist. That is, from the resting state, a partial agonist initiates somewhat of an increase in the signal transduction cascade from the G-protein-linked second-messenger system. However, when full agonist neurotransmitter is present, the same partial agonist will become a net antagonist. That is, it will decrease the level of full signal output to a lesser level, but not to zero. Thus, a partial agonist can simultaneously boost deficient neurotransmitter activity yet block excessive neurotransmitter activity, another reason that partial agonists are called stabilizers.
Returning to the light-switch analogy, a room will be dark when agonist is missing and the light switch is off (Figure 2-8C). A room will be brightly lit when it is full of natural full agonist and the light switch is fully on (Figure 2-8A). Adding partial agonist to the dark room where there is no natural full agonist neurotransmitter will turn the lights up, but only as far as the partial agonist works on the rheostat (Figure 2-8B). Relative to the dark room as a starting point, a partial agonist acts therefore as a net agonist. On the other hand, adding a partial agonist to the fully lit room will have the effect of turning the lights down to the intermediate level of lower brightness on the rheostat (Figure 2-8B). This is a net antagonistic effect relative to the fully lit room. Thus, after adding partial agonist to the dark room and to the brightly lit room, both rooms will be equally light. The degree of brightness is that of being partially turned on, as dictated by the properties of the partial agonist. However, in the dark room, the partial agonist has acted as a net agonist, whereas in the brightly lit room, the partial agonist has acted as a net antagonist.
An agonist and an antagonist in the same molecule is quite a new dimension to therapeutics. This concept has led to proposals that partial agonists could treat not only states that are theoretically deficient in full agonist, but also those that have a theoretical excess of full agonist. A partial agonist may even be able to treat simultaneously states that are mixtures of both excess and deficiency in neurotransmitter activity.
Inverse agonists
Inverse agonists are more than simple antagonists, and are neither neutral nor silent. These agents have an action that is thought to produce a conformational change in the G-protein-linked receptor that stabilizes it in a totally inactive form (Figure 2-9). Thus, this conformation produces a functional reduction in signal transduction (Figure 2-9) that is even less than that produced when there is either no agonist present (Figure 2-4) or a silent antagonist present (Figure 2-6). The result of an inverse agonist is to shut down even the constitutive activity of the G-protein-linked receptor system. Of course, if a given receptor system has no constitutive activity, perhaps in cases when receptors are present in low density, then there will be no reduction in activity and the inverse agonist will look like an antagonist.
Figure 2-9. Inverse agonist. Inverse agonists produce conformational change in the G-protein-linked receptor that renders it inactive. This leads to reduced signal transduction as compared not only to that associated with agonists but also to that associated with antagonists or the absence of an agonist. The impact of an inverse agonist is dependent on the receptor density in that brain region. That is, if the receptor density is so low that constitutive activity does not lead to detectable signal transduction, then reducing the constitutive activity would not have any appreciable effect.
In many ways, therefore, inverse agonists do the opposite of agonists. If an agonist increases signal transduction from baseline, an inverse agonist decreases it, even below baseline levels. In contrast to agonists and antagonists, therefore, an inverse agonist neither increases signal transduction like an agonist (Figure 2-5) nor merely blocks the agonist from increasing signal transduction like an antagonist (Figure 2-6); rather, an inverse agonist binds the receptor in a fashion so as to provoke an action opposite to that of the agonist, namely causing the receptor to decrease its baseline signal transduction level (Figure 2-9). It is unclear from a clinical point of view what the relevant differences are between an inverse agonist and a silent antagonist. In fact, some drugs that have long been considered to be silent antagonists may turn out in some areas of the brain to be inverse agonists. Thus, the concept of an inverse agonist as clinically distinguishable from a silent antagonist remains to be proven. In the meantime, inverse agonists remain an interesting pharmacological concept.
In summary, G-protein-linked receptors act along an agonist spectrum, and drugs have been described that can produce conformational changes in these receptors to create any state from full agonist, to partial agonist, to silent antagonist, to inverse agonist (Figure 2-10). When one considers signal transduction along this spectrum (Figure 2-10), it is easy to understand why agents at each point along the agonist spectrum differ so much from each other, and why their clinical actions are so different.
Figure 2-10. Agonist spectrum. This figure summarizes the implications of the agonist spectrum. Full agonists cause maximum signal transduction, while partial agonists increase signal transduction compared to no agonist but decrease it compared to full agonist. Antagonists allow constitutive activity and thus, in the absence of an agonist, have no effects themselves; in the presence of an agonist, antagonists lead to reduced signal transduction. Inverse agonists are the functional opposites of agonists and actually reduce signal transduction beyond that produced in the absence of an agonist.
Enzymes as targets of psychotropic drugs
Enzymes are involved in multiple aspects of chemical neurotransmission, as discussed extensively in Chapter 1 on signal transduction. Every enzyme is the theoretical target for a drug acting as an enzyme inhibitor. However, in practice, only a minority of currently known drugs utilized in the clinical practice of psychopharmacology are enzyme inhibitors.
Enzyme activity is the conversion of one molecule into another, namely a substrate into a product (Figure 2-11). The substrates for each enzyme are unique and selective, as are the products. A substrate (Figure 2-11A) comes to the enzyme to bind at the enzyme’s active site (Figure 2-11B), and departs as a changed molecular entity called the product (Figure 2-11C). The inhibitors of an enzyme are also unique and selective for one enzyme compared to another. In the presence of an enzyme inhibitor, the enzyme cannot bind to its substrates. The binding of inhibitors can be either irreversible (Figure 2-12) or reversible (Figure 2-13).
Figure 2-11. Enzyme activity. Enzyme activity is the conversion of one molecule into another. Thus, a substrate is said to be turned into a product by enzymatic modification of the substrate molecule. The enzyme has an active site at which the substrate can bind specifically (A). The substrate then finds the active site of the enzyme and binds to it (B), so that a molecular transformation can occur, changing the substrate into the product (C).
Figure 2-12. Irreversible enzyme inhibitors. Some drugs are inhibitors of enzymes. Shown here is an irreversible inhibitor of an enzyme, depicted as binding to the enzyme with chains (A). A competing substrate cannot remove an irreversible inhibitor from the enzyme, depicted as scissors unsuccessfully attempting to cut the chains off the inhibitor (B). The binding is locked so permanently that such irreversible enzyme inhibition is sometimes called the work of a “suicide inhibitor,” since the enzyme essentially commits suicide by binding to the irreversible inhibitor. Enzyme activity cannot be restored unless another molecule of enzyme is synthesized by the cell’s DNA.
Figure 2-13. Reversible enzyme inhibitors. Other drugs are reversible enzyme inhibitors, depicted as binding to the enzyme with a string (A). A reversible inhibitor can be challenged by a competing substrate for the same enzyme. In the case of a reversible inhibitor, the molecular properties of the substrate are such that it can get rid of the reversible inhibitor, depicted as scissors cutting the string that binds the reversible inhibitor to the enzyme (B). The consequence of a substrate competing successfully for reversal of enzyme inhibition is that the substrate displaces the inhibitor and shoves it off (C). Because the substrate has this capability, the inhibition is said to be reversible.
When an irreversible inhibitor binds to the enzyme, it cannot be displaced by the substrate; thus, that inhibitor binds irreversibly (Figure 2-12). This is depicted as binding with chains (Figure 2-12A) that cannot be cut with scissors by the substrate (Figure 2-12B). The irreversible type of enzyme inhibitor is sometimes called a “suicide inhibitor” because it covalently and irreversibly binds to the enzyme protein, permanently inhibiting it and therefore essentially “killing” it by making the enzyme nonfunctional forever (Figure 2-12). Enzyme activity in this case is only restored when new enzyme molecules are synthesized.
However, in the case of reversible enzyme inhibitors, an enzyme’s substrate is able to compete with that reversible inhibitor for binding to the enzyme, and shove it off the enzyme (Figure 2-13). Whether the substrate or the inhibitor “wins” or predominates depends upon which one has the greater affinity for the enzyme and/or is present in the greater concentration. Such binding is called “reversible.” Reversible enzyme inhibition is depicted as binding with strings (Figure 2-13A), such that the substrate can cut them with scissors (Figure 2-13B) and displace the enzyme inhibitor, then bind the enzyme itself with its own strings (Figure 2-13C).
These concepts can be applied potentially to any enzyme system. Several enzymes are involved in neurotransmission, including in the synthesis and destruction of neurotransmitters as well as in signal transduction. Only three enzymes are known to be targeted by psychotropic drugs currently used in clinical practice, namely monoamine oxidase (MAO), acetylcholinesterase, and glycogen synthase kinase (GSK). MAO inhibitors are discussed in more detail in Chapter 7 on antidepressants, and acetylcholinesterase inhibitors are discussed in more detail in Chapter 13 on cognition. Lithium may target an important enzyme in the signal transduction pathway of neurotrophic factors (Figure 2-14). That is, some neurotrophins, growth factors, and other signaling pathways act through a specific downstream phosphoprotein, an enzyme called GSK-3, to promote cell death (proapoptotic actions). Lithium has the capacity to inhibit this enzyme (Figure 2-14). It is possible that inhibition of this enzyme is physiologically relevant, because this action could lead to neuroprotective actions and long-term plasticity and may contribute to the antimanic and mood-stabilizing actions known to be associated with lithium. The development of novel GSK-3 inhibitors is in progress.
Figure 2-14. Receptor tyrosine kinases. Receptor tyrosine kinases are potential targets for novel psychotropic drugs. Left: Some neurotrophins, growth factors, and other signaling pathways act through a downstream phosphoprotein, an enzyme called GSK-3 (glycogen synthase kinase), to promote cell death (proapoptotic actions). Right: Lithium and possibly some other mood stabilizers may inhibit this enzyme, which could lead to neuroprotective actions and long-term plasticity as well as possibly contribute to mood-stabilizing actions.
Cytochrome P450 drug metabolizing enzymes as targets of psychotropic drugs
Pharmacokinetic actions are mediated through the hepatic and gut drug metabolizing system known as the cytochrome P450 (CYP) enzyme system. Pharmacokinetics is the study of how the body acts upon drugs, especially to absorb, distribute, metabolize, and excrete them. The CYP enzymes and the pharmacokinetic actions they represent must be contrasted with the pharmacodynamic actions of drugs, the latter being the major emphasis of this book. Pharmacodynamic actions account for the therapeutic effects and side effects of drugs. However, many psychotropic drugs also target the CYP drug metabolizing enzymes, and a brief overview of these enzymes and their interactions with psychotropic drugs is in order.
CYP enzymes follow the same principles of enzymes transforming substrates into products as illustrated in Figures 2-11 through 2-13. Figure 2-15 depicts the concept of a psychotropic drug being absorbed through the gut wall on the left and then sent to the big blue enzyme in the liver to be biotransformed so that the drug can be sent back into the bloodstream to be excreted from the body via the kidney. Specifically, CYP enzymes in the gut wall or liver convert the drug substrate into a biotransformed product in the bloodstream. After passing through the gut wall and liver, the drug will exist partially as unchanged drug and partially as biotransformed product in the bloodstream (Figure 2-15).
Figure 2-15. Cytochrome P450. The cytochrome P450 (CYP) enzyme system mediates how the body metabolizes many drugs, including antipsychotics. The CYP enzyme in the gut wall or liver converts the drug into a biotransformed product in the bloodstream. After passing through the gut wall and liver (left), the drug will exist partly as unchanged drug and partly as biotransformed drug (right).
There are several known CYP systems. Five of the most important enzymes for antidepressant drug metabolism are shown in Figure 2-16. There are over 30 known CYP enzymes, and probably many more awaiting discovery and classification. Not all individuals have all the same CYP enzymes. In such cases, their enzymes are said to be polymorphic. For example, about 5–10% of Caucasians are poor metabolizers via the enzyme CYP 2D6, and approximately 20% of Asians may have reduced activity of another CYP enzyme, 2C19. Such individuals with genetically low enzyme activity must metabolize drugs by alternative routes that may not be as efficient as the traditional routes; thus, these patients often have elevated drug levels in their bloodstreams and in their brains compared to individuals with normal enzyme activity. Other individuals may inherit a CYP enzyme that is extensively active compared to normal enzyme activity, and thus have lower drug levels compared to patients with normal enzyme activity. The genes for these CYP enzymes can now be measured and can be used to predict which patients might need to have up or down dosage adjustments of certain drugs for best results.
Figure 2-16. Five CYP enzymes. There are many cytochrome P450 (CYP) systems; these are classified according to family, subtype, and gene product. Five of the most important are shown here: CYP 1A2, 2D6, 2C9, 2C19, and 3A4.
CYP 1A2
One important CYP enzyme is 1A2. Several antipsychotics and antidepressants are substrates for 1A2, as are caffeine and theophylline (Figure 2-17). An inhibitor of 1A2 is the antidepressant fluvoxamine (Figure 2-17). This means that when substrates of 1A2, such as olanzapine, clozapine, zotepine, asenapine, duloxetine, or theophylline, are given concomitantly with an inhibitor of 1A2, such as fluvoxamine, the blood and brain levels of 1A2 substrates could rise (Figure 2-17). Although this may not be particularly clinically important for olanzapine or asenapine (possibly causing slightly increased sedation), it could potentially raise plasma levels sufficiently in the case of clozapine, zotepine, duloxetine, or theophylline to increase side effects, including possibly increasing the risk of seizures. Thus, the dose of clozapine or zotepine (or olanzapine and asenapine, as well as duloxetine) may need to be lowered when administered with fluvoxamine, or an antidepressant other than fluvoxamine may need to be chosen.
Figure 2-17. Consequences of CYP 1A2 inhibition. Numerous drugs (theophylline, duloxetine, clozapine, olanzapine, zotepine, asenapine, certain tricyclic antidepressants (TCAs), and agomelatine) are substrates for CYP 1A2. Thus, in the presence of a CYP 1A2 inhibitor (fluvoxamine, ciprofloxacin) their levels will rise. In many cases, this means that the dose of the substrate must often be lowered in order to avoid side effects.
1A2 can also be induced, or increased in activity, by smoking. When patients smoke, any substrate of 1A2 may have its blood and brain levels fall and require more dosage. Also, patients stabilized on an antipsychotic dose who start smoking may relapse if the drug levels fall too low. Cigarette smokers may require higher doses of 1A2 substrates than nonsmokers (Figure 2-18).
Figure 2-18. CYP 1A2 and smoking. Cigarette smoking, quite common among patients with schizophrenia, can induce the enzyme CYP 1A2 and lower the concentration of drugs metabolized by this enzyme, such as olanzapine, clozapine, zotepine, and others. Smokers may also require higher doses of these drugs than nonsmokers.
CYP 2D6
Another CYP enzyme of importance to many psychotropic drugs is 2D6. Many antipsychotics and some antidepressants are substrates for 2D6, and several antidepressants are also inhibitors of this enzyme (Figure 2-19). This enzyme converts two drugs, risperidone and venlafaxine, into active drugs (i.e., paliperidone and desvenlafaxine, respectively) rather than inactive metabolites. Giving a substrate of 2D6 to a patient who is either a genetically poor metabolizer of this enzyme or who is taking an inhibitor of 2D6 can raise the blood and brain levels of the substrate. This can be especially important for patients taking the 2D6 substrates tricyclic antidepressants, atomoxetine, thioridazine, iloperidone, and codeine, for example, so dose adjustments or using an alternative drug may be necessary for maximum safety and efficacy. Asenapine is an inhibitor of 2D6 and can raise the levels of drugs that are substrates of 2D6.
Figure 2-19. Consequences of CYP 2D6 inhibition. If a tricyclic antidepressant (a substrate for CYP 2D6) is given concomitantly with an agent that is an inhibitor of CYP 2D6 (e.g., paroxetine, fluoxetine), this will cause the levels of the tricyclic antidepressant to increase, which can be toxic. Therefore either monitoring of tricyclic plasma concentration with dose reduction or avoidance of this combination is required. Many other psychotropic medications are also substrates for CYP 2D6 and may therefore have increased blood levels when given with a CYP 2D6 inhibitor.
CYP 3A4
This enzyme metabolizes several psychotropic drugs as well as several of the HMG-CoA reductase inhibitors (statins) for treating high cholesterol (Figure 2-20). Several psychotropic drugs are weak inhibitors of this enzyme, including the antidepressants fluvoxamine, nefazodone, and the active metabolite of fluoxetine, norfluoxetine (Figure 2-20). Several nonpsychotropic drugs are powerful inhibitors of 3A4, including ketoconazole (antifungal), protease inhibitors (for AIDS/HIV), and erythromycin (antibiotic) (Figure 2-20). For the substrates of 3A4, co-administration of a 3A4 inhibitor may require dosage reduction of the substrate. Specifically, combining a 3A4 inhibitor with the 3A4 substrate pimozide can result in elevated plasma pimozide levels, with consequent QTc prolongation and dangerous cardiac arrhythmias. Combining a 3A4 inhibitor with alprazolam or triazolam can cause significant sedation due to elevated plasma drug levels of these latter agents. Combining a 3A4 inhibitor with certain cholesterol-lowering drugs that are 3A4 substrates (e.g., simvastatin, atorvastatin, lovastatin, or cerevastatin, but not pravastatin or fluvastatin) can increase the risk of muscle damage and rhabdomyolysis from elevated plasma levels of these statins.
Figure 2-20. Substrates and inhibitors for CYP 3A4. The antipsychotic pimozide, the benzodiazepines alprazolam and triazolam, the anxiolytic buspirone, HMG-CoA reductase inhibitors (statins), and multiple antipsychotics are all substrates for CYP 3A4. Fluvoxamine, fluoxetine, and nefazodone are moderate CYP 3A4 inhibitors, as are some nonpsychotropic agents.
There are also some drugs that can induce 3A4, including carbamazepine, rifampin, and some reverse transcriptase inhibitors for HIV/AIDS (Figure 2-21). Since carbamazepine is a mood stabilizer frequently mixed with atypical antipsychotics, it is possible that carbamazepine added to the regimen of a patient previously stabilized on clozapine, quetiapine, ziprasidone, sertindole, aripiprazole, iloperidone, lurasidone, or zotepine could reduce the blood and brain levels of these agents, requiring their doses to be increased. On the other hand, if carbamazepine is stopped in a patient receiving one of these atypical antipsychotics, their doses may need to be reduced, because the autoinduction of 3A4 by carbamazepine will reverse over time.
Figure 2-21. CYP 3A4 induced by carbamazepine. The enzyme CYP 3A4 can be induced by the anticonvulsant and mood stabilizer carbamazepine, as well as by rifampin and some reverse transcriptase inhibitors. This would lead to increased metabolism of substrates for 3A4 (e.g., clozapine, quetiapine, ziprasidone, sertindole, aripiprazole, and zotepine) and may therefore require higher doses of these agents when given concomitantly with carbamazepine.
Drug interactions mediated by CYP enzymes are constantly being discovered, and the active clinician who combines drugs must be alert to these, and thus be continually updated on what drug interactions are important. Here we present only the general concepts of drug interactions at CYP enzyme systems, but the specifics should be found in a comprehensive and up-to-date reference source (such as Stahl’s Essential Psychopharmacology: the Prescriber’s Guide, a companion to this textbook) before prescribing.
Summary
About a third of psychotropic drugs in clinical practice bind to a neurotransmitter transporter, and another third of psychotropic drugs bind to G-protein-linked receptors. These two molecular sites of action, their impact upon neurotransmission, and various specific drugs that act at these sites have all been reviewed in this chapter.
Specifically, there are two subclasses of plasma membrane transporters for neurotransmitters and three subclasses of intracellular synaptic vesicular transporters for neurotransmitters. The monoamine transporters (SERT for serotonin, NET for norepinephrine, and DAT for dopamine) are key targets for most of the known antidepressants. In addition, stimulants target DAT. The vesicular transporter for all three of these monoamines is known as VMAT2 (vesicular monoamine transporter 2) and is also a target of the stimulant amphetamine.
G-protein receptors are the most common targets of psychotropic drugs, and their actions can lead to both therapeutic and side effects. Drug actions at these receptors occur in a spectrum, from full agonist actions, to partial agonist actions, to antagonism, and even to inverse agonism. Natural neurotransmitters are full agonists, as are some drugs used in clinical practice. However, most drugs that act directly on G-protein-linked receptors act as antagonists. A few act as partial agonists, and some as inverse agonists. Each drug interacting at a G-protein-linked receptor causes a conformational change in that receptor that defines where on the agonist spectrum it will act. Thus, a full agonist produces a conformational change that turns on signal transduction and second-messenger formation to the maximum extent. One novel concept is that of a partial agonist, which acts somewhat like an agonist, but to a lesser extent. An antagonist causes a conformational change that stabilizes the receptor in the baseline state and thus is “silent.” In the presence of agonists or partial agonists, an antagonist causes the receptor to return to this baseline state as well, and thus reverses their actions. A novel receptor action is that of an inverse agonist that leads to a conformation of the receptor that stops all activity, even baseline actions. Understanding the agonist spectrum can lead to prediction of downstream consequences on signal transduction, including clinical actions.